Nintedanib

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Overview

Description: A medication used to treat lung diseases that involve scarring of the lung tissue and a certain type of lung cancer.
Structure
Description: A medication used to treat lung diseases that involve scarring of the lung tissue and a certain type of lung cancer.
DrugBank ID: DB09079
Type: Small Molecule
US Approved: YES
Other Approved: YES
Patents: 6
Indicated Conditions: 6
Clinical Trials: Phase 0
0
Phase 1
97
Phase 2
78
Phase 3
25
Phase 4
12
Therapeutic Categories: Antifibrotic Agents

Kinase Inhibitor
Mechanism of Action: Vascular endothelial growth factor receptor 1
Inhibitor

Vascular endothelial growth factor receptor 2
Inhibitor

Vascular endothelial growth factor receptor 3
Inhibitor

+ 5 more targets

Identification

Summary

Nintedanib is a triple angiokinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and in combination with docetaxel for non-small cell lung cancer.

Brand Names

Ofev, Vargatef

Generic Name

Nintedanib

DrugBank Accession Number

DB09079

Background

Nintedanib is a small molecule kinase inhibitor used in the treatment of pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and non-small cell lung cancer (NSCLC).^8,9 It was first approved for use in the United States in 2014.⁸ Within the spectrum of idiopathic pulmonary fibrosis treatment options, nintedanib is currently one of only two disease-modifying therapies available and indicated for the condition (the other being Pirfenidone) and as such is used as a first-line treatment following diagnosis to slow down the progressive loss of lung function.⁶ As a chemotherapeutic agent for NSCLC, nintedanib, in combination with Docetaxel, is reserved for patients who have tried and failed first-line chemotherapeutic options.⁹

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 539.6248
Monoisotopic: 539.253254569
Chemical Formula: C₃₁H₃₃N₅O₄

Synonyms

methyl (3Z)-3-[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}anilino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
Nintedanib

External IDs

BIBF 1120
BIBF-1120
BIBF1120

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Pharmacology

Indication

Nintedanib is indicated for the treatment of idiopathic pulmonary fibrosis (IPF)⁸ and to slow declining pulmonary function in patients with systemic sclerosis-associated interstitial lung disease.¹⁰ It is also indicated for the treatment of chronic fibrosing interstitial lung diseases with a progressive phenotype.¹⁰

In the EU, under the brand name Vargatef, nintedanib is indicated in combination with docetaxel for the treatment of adult patients with metastatic, locally advanced, or locally recurrent non-small cell lung cancer of adenocarcinoma histology who have already tried first-line therapy.⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Dose Form
Management of	Decreased pulmonary function		••••••••••••	•••••	•••••••
Treatment of	Idiopathic pulmonary fibrosis		••••••••••••	•••••	•••••••
Treatment of	Chronic progressive fibrosing interstitial lung disease		••••••••••••	•••••	•••••••
Used in combination to treat	Locally advanced non-small cell lung carcinoma (nsclc)	Regimen in combination with: Docetaxel (DB01248)	••••••••••••	•••••	•••••••
Used in combination to treat	Locally recurrent non-small cell lung carcinoma (nsclc)	Regimen in combination with: Docetaxel (DB01248)	••••••••••••	•••••	•••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Nintedanib is a small molecule kinase inhibitor that inhibits upstream kinase activity to ultimately inhibit lung fibroblast proliferation and migration, as well as signalling pathways that promote the proliferation and survival of endothelial and perivascular cells in tumour tissues.^8,9,5

Nintedanib poses a risk of drug-induced liver injury, especially within the first three months of therapy.^8,9 Liver function tests should be conducted at baseline prior to beginning therapy, at regular intervals for the first three months of therapy, and as indicated thereafter in patients exhibiting symptoms of hepatic injury such as jaundice or right upper quadrant pain. It is not recommended to be used in patients with pre-existing moderate to severe hepatic impairment (Child Pugh class B or C).

Mechanism of action

Nintedanib is a small molecule, competitive, triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are implicated in lung fibrosis and tumour angiogenesis, so nintedanib is therefore used in the treatment of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease.^8,9 The specific RTKs that nintedanib inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fns-Like tyrosine kinase-3 (FLT3).^8,9,5 Nintedanib binds to the ATP-binding pocket of these receptors and inhibits their activity, thereby blocking signalling cascades that result in the proliferation and migration of lung fibroblasts. Nintedanib also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis, culminating in an inhibition of cell proliferation and apoptosis of affected tumour cells.⁵

In addition to RTK inhibition, nintedanib also prevents the actions of the nRTKs Lck, Lyn, and Src.^8,9,5 The contribution of the inhibition of Lck and Lyn towards the therapeutic efficacy of nintedanib is unclear, but inhibition of the Src pathway by nintedanib has been shown to reduce lung fibrosis.^5,7

Target	Actions	Organism
AVascular endothelial growth factor receptor 1	inhibitor	Humans
AVascular endothelial growth factor receptor 2	inhibitor	Humans
AVascular endothelial growth factor receptor 3	inhibitor	Humans
APlatelet-derived growth factor receptor alpha	inhibitor	Humans
APlatelet-derived growth factor receptor beta	inhibitor	Humans
AFibroblast growth factor receptor 1	inhibitor	Humans
AFibroblast growth factor receptor 2	inhibitor	Humans
AFibroblast growth factor receptor 3	inhibitor	Humans
UReceptor-type tyrosine-protein kinase FLT3	inhibitor	Humans
UTyrosine-protein kinase Lck	inhibitor	Humans
UTyrosine-protein kinase Lyn	inhibitor	Humans
UProto-oncogene tyrosine-protein kinase Src	inhibitor	Humans

Absorption

The absolute bioavailability of nintedanib is low at approximately 4.7%, likely owing to substantial first-pass metabolism and the effects of p-glycoprotein (P-gp) transporters.^8,9,5 T_max following oral administration is reached after approximately 2 hours in fasted patients and approximately 4 hours in fed patients, regardless of the food consumed.^8,9 Administration of nintedanib following a high-fat, high-calorie meal resulted in an increase in C_max by approximately 15% and an increase in AUC by approximately 20%.⁵ Age, body weight, and smoking status have been found to alter exposure to nintedanib, but these effects are not significant enough to warrant dose alterations.^8,5

Volume of distribution

Nintedanib appears to follow biphasic disposition kinetics - the observed volume of distribution following intravenous administration is 1050 L^8,9, indicating extensive distribution into peripheral tissues. In rats, nintedanib was shown to rapidly and homogeneously distribute into peripheral tissues with the exception of the CNS, suggestive of an inability of nintedanib to cross the blood-brain barrier.⁵

Protein binding

Plasma protein binding of nintedanib is high, with a bound fraction of 97.8%. Albumin is thought to be the major binding protein.^8,9,5

Metabolism

Nintedanib is predominantly metabolized via hydrolytic cleavage by esterases to its principle metabolite, BIBF 1202, which then undergoes glucuronidation via UGT enzymes in the intestines and liver (specifically UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10) to form BIBF 1202 glucuronide.^8,9,5 The CYP450 enzyme system plays a minor role in nintedanib metabolism, with CYP3A4 believed to be the main contributor - the major CYP-dependent metabolite of nintedanib, a demethylated metabolite termed BIBF 1053, could not be detected in plasma during pharmacokinetic studies and was found only in small quantities in the feces (approximately 4% of total dose).⁵ CYP-dependent metabolism of nintedanib accounts for roughly 5% of total drug metabolism, as opposed to 25% for esterase cleavage.^8,9 Other minor metabolites, M7 and M8, are found in very small quantities in the urine (0.03% and 0.01%, respectively), though their origin and relevance is currently unclear.⁵

Hover over products below to view reaction partners

Nintedanib
- BIBF 1202
  - BIBF 1202 glucuronide
- BIBF 1053
  - Nintedanib M4 Metabolite

Route of elimination

Nintedanib is eliminated primarily via fecal and biliary excretion, with 93.4% of radio labelled nintedanib found in feces within 120 hours following administration.^8,9,5 Renal clearance accounts for a small portion of nintedanib's elimination, approximately 0.65% of the total dose, and excretion of unchanged nintedanib 48 hours after oral and intravenous doses was 0.05% and 1.4%, respectively.^8,9,5

Half-life

The terminal elimination half-life of nintedanib is approximately 10-15 hours.^9,5 In patients with idiopathic pulmonary fibrosis, the effective half-life of nintedanib has been estimated to be approximately 9.5 hours.^8,5

Clearance

Nintedanib is has a high total plasma clearance of approximately 1390 mL/min and a renal clearance of 20 mL/min.⁸

Adverse Effects

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Toxicity

Experience with nintedanib overdose is limited, but patients who inadvertently received higher-than-intended doses during initial trials experienced adverse effects consistent with the known safety profile of nintedanib, for example elevated liver enzymes and significant gastrointestinal effects.^8,9

There are no specific guidelines for the treatment of nintedanib overdose - in this case, therapy should be interrupted and general supportive measures employed as indicated.^8,9

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

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Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abametapir	The serum concentration of Nintedanib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Nintedanib can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Nintedanib is combined with Abciximab.
Abemaciclib	The metabolism of Abemaciclib can be decreased when combined with Nintedanib.
Abrocitinib	The serum concentration of Nintedanib can be increased when it is combined with Abrocitinib.

Food Interactions

Take with food. Co-administration with food improves absorption.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Nintedanib esylate	42F62RTZ4G	656247-18-6	MMMVNAGRWOJNMW-FJBFXRHMSA-N

International/Other Brands

Vargatef (Boehringer-Ingelheim)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Eugia-nintedanib	Capsule	150 mg	Oral	Eugia Pharma (Malta) Limited	Not applicable	Not applicable
Eugia-nintedanib	Capsule	100 mg	Oral	Eugia Pharma (Malta) Limited	Not applicable	Not applicable
Nintedanib Accord	Capsule	150 mg	Oral	Accord Healthcare, S.L.U.	2024-07-10	Not applicable
Nintedanib Accord	Capsule	100 mg	Oral	Accord Healthcare, S.L.U.	2024-07-10	Not applicable
Nintedanib Accord	Capsule	100 mg	Oral	Accord Healthcare, S.L.U.	2024-07-10	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Auro-nintedanib	Capsule	100 mg	Oral	Auro Pharma Inc	Not applicable	Not applicable
Auro-nintedanib	Capsule	150 mg	Oral	Auro Pharma Inc	Not applicable	Not applicable
Jamp Nintedanib	Capsule	150 mg	Oral	Jamp Pharma Corporation	Not applicable	Not applicable

Chemical Identifiers

UNII: G6HRD2P839
CAS number: 656247-17-5
InChI Key: XZXHXSATPCNXJR-ZIADKAODSA-N
InChI: InChI=1S/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,32H,15-18,20H2,1-3H3,(H,33,38)/b29-28-
IUPAC Name: methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate
SMILES: COC(=O)C1=CC=C2C(NC(=O)\C2=C(/NC2=CC=C(C=C2)N(C)C(=O)CN2CCN(C)CC2)C2=CC=CC=C2)=C1

References

Synthesis Reference

Gerald J. Roth, Armin Heckel, Florian Colbatzky, Sandra Handschuh, Jörg Kley, Thorsten Lehmann-Lintz, Ralf Lotz, Ulrike Tontsch-Grunt, Rainer Walter, and Frank Hilberg Journal of Medicinal Chemistry 2009 52 (14), 4466-4480 DOI: 10.1021/jm900431g

General References

Keating GM: Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis. Drugs. 2015 Jul;75(10):1131-40. doi: 10.1007/s40265-015-0418-6. [Article]
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Mazzei ME, Richeldi L, Collard HR: Nintedanib in the treatment of idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 2015 Jun;9(3):121-9. doi: 10.1177/1753465815579365. Epub 2015 Apr 10. [Article]
Stopfer P, Rathgen K, Bischoff D, Ludtke S, Marzin K, Kaiser R, Wagner K, Ebner T: Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers. Xenobiotica. 2011 Apr;41(4):297-311. doi: 10.3109/00498254.2010.545452. Epub 2011 Jan 4. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
Richeldi L, Collard HR, Jones MG: Idiopathic pulmonary fibrosis. Lancet. 2017 May 13;389(10082):1941-1952. doi: 10.1016/S0140-6736(17)30866-8. Epub 2017 Mar 30. [Article]
Li LF, Kao KC, Liu YY, Lin CW, Chen NH, Lee CS, Wang CW, Yang CT: Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway. J Cell Mol Med. 2017 Nov;21(11):2937-2949. doi: 10.1111/jcmm.13206. Epub 2017 Jun 9. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]
EMA Summary of Product Characteristics: Vargatef (nintedanib) soft capsules for oral use [Link]
FDA New Indication Approval: Nintedanib [Link]

External Links

KEGG Drug: D10481
PubChem Compound: 9809715
PubChem Substance: 310265007
ChemSpider: 7985471
BindingDB: 50026612
RxNav: 1592737
ChEBI: 85164
ChEMBL: CHEMBL502835
ZINC: ZINC000100014909
PDBe Ligand: XIN
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Nintedanib

PDB Entries

3c7q / 5maf / 5te0 / 6nec

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Active Not Recruiting	Not Available	Idiopathic Pulmonary Fibrosis (IPF)	1	somestatus	stop reason	just information to hide
Not Available	Active Not Recruiting	Not Available	Interstitial Lung Disease	3	somestatus	stop reason	just information to hide
Not Available	Approved for Marketing	Not Available	Idiopathic Pulmonary Fibrosis (IPF)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Idiopathic Pulmonary Fibrosis (IPF)	9	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Interstitial Lung Disease	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule	Oral
Capsule	Oral	100 mg/1
Capsule	Oral	150 mg/1
Capsule	Oral	150.00 mg
Capsule	Oral	100 mg
Capsule	Oral	150 mg
Capsule, liquid filled	Oral	150 mg
Capsule, liquid filled	Oral	100 mg
Capsule	Oral	100.000 mg
Capsule, gelatin coated	Oral	100 MG
Capsule, gelatin coated	Oral	150 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US7989474	No	2011-08-02	2024-04-06
US7119093	No	2006-10-10	2024-02-21
US6762180	Yes	2004-07-13	2026-04-01
US9907756	Yes	2018-03-06	2029-12-07
US10105323	Yes	2018-10-23	2029-12-04
US10154990	Yes	2018-12-18	2026-07-08

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0309 mg/mL	ALOGPS
logP	3.7	ALOGPS
logP	2.79	Chemaxon
logS	-4.2	ALOGPS
pKa (Strongest Acidic)	10.86	Chemaxon
pKa (Strongest Basic)	7.23	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	94.22 Å²	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	159.1 m³·mol^-1	Chemaxon
Polarizability	58.79 Å³	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0006-0000090000-f18cac7251efc2885ad3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4s-0004190000-658c819b623d79b5bb8c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-052f-0300190000-a6810589012e6e9e34bc
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0202490000-747eebdc6e7126182871
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-02u3-4924230000-288ba353512dd0a79d24
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-07be-2208940000-013b5feebdc1df0d17cd

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	221.033	predicted	DeepCCS 1.0 (2019)
[M+H]+	223.14182	predicted	DeepCCS 1.0 (2019)
[M+Na]+	229.05345	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Vascular endothelial growth factor receptor 1

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. Acts as a positive regulator of postnatal retinal hyaloid vessel regression (By similarity). May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1 (PubMed:16685275)
Specific Function: ATP binding
Gene Name: FLT1
Uniprot ID: P17948
Uniprot Name: Vascular endothelial growth factor receptor 1
Molecular Weight: 150767.185 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details2. Vascular endothelial growth factor receptor 2

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC
Specific Function: ATP binding
Gene Name: KDR
Uniprot ID: P35968
Uniprot Name: Vascular endothelial growth factor receptor 2
Molecular Weight: 151525.555 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details3. Vascular endothelial growth factor receptor 3

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'
Specific Function: ATP binding
Gene Name: FLT4
Uniprot ID: P35916
Uniprot Name: Vascular endothelial growth factor receptor 3
Molecular Weight: 152755.94 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details4. Platelet-derived growth factor receptor alpha

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor
Specific Function: ATP binding
Gene Name: PDGFRA
Uniprot ID: P16234
Uniprot Name: Platelet-derived growth factor receptor alpha
Molecular Weight: 122668.46 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details5. Platelet-derived growth factor receptor beta

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Plays a role in the migration of vascular smooth muscle cells and the formation of neointima at vascular injury sites. Required for normal development of the cardiovascular system. Required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. Promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. Binding of its cognate ligands - homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFD -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PLCG1, PIK3R1, PTPN11, RASA1/GAP, CBL, SHC1 and NCK1. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to the activation of the AKT1 signaling pathway. Phosphorylation of SHC1, or of the C-terminus of PTPN11, creates a binding site for GRB2, resulting in the activation of HRAS, RAF1 and down-stream MAP kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation and activation of SRC family kinases. Promotes phosphorylation of PDCD6IP/ALIX and STAM. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor
Specific Function: ATP binding
Gene Name: PDGFRB
Uniprot ID: P09619
Uniprot Name: Platelet-derived growth factor receptor beta
Molecular Weight: 123966.895 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details6. Fibroblast growth factor receptor 1

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation
Specific Function: ATP binding
Gene Name: FGFR1
Uniprot ID: P11362
Uniprot Name: Fibroblast growth factor receptor 1
Molecular Weight: 91866.935 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details7. Fibroblast growth factor receptor 2

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic development. Required for normal embryonic patterning, trophoblast function, limb bud development, lung morphogenesis, osteogenesis and skin development. Plays an essential role in the regulation of osteoblast differentiation, proliferation and apoptosis, and is required for normal skeleton development. Promotes cell proliferation in keratinocytes and immature osteoblasts, but promotes apoptosis in differentiated osteoblasts. Phosphorylates PLCG1, FRS2 and PAK4. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. FGFR2 signaling is down-regulated by ubiquitination, internalization and degradation. Mutations that lead to constitutive kinase activation or impair normal FGFR2 maturation, internalization and degradation lead to aberrant signaling. Over-expressed FGFR2 promotes activation of STAT1.
Specific Function: ATP binding
Gene Name: FGFR2
Uniprot ID: P21802
Uniprot Name: Fibroblast growth factor receptor 2
Molecular Weight: 92024.29 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details8. Fibroblast growth factor receptor 3

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling
Specific Function: ATP binding
Gene Name: FGFR3
Uniprot ID: P22607
Uniprot Name: Fibroblast growth factor receptor 3
Molecular Weight: 87708.905 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details9. Receptor-type tyrosine-protein kinase FLT3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways
Specific Function: ATP binding
Gene Name: FLT3
Uniprot ID: P36888
Uniprot Name: Receptor-type tyrosine-protein kinase FLT3
Molecular Weight: 112902.51 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details10. Tyrosine-protein kinase Lck

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Non-receptor tyrosine-protein kinase that plays an essential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells. Plays a key role in T-cell antigen receptor (TCR)-linked signal transduction pathways. Constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, thereby recruiting the associated LCK protein to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the cytoplasmic tails of the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. Once stimulated, the TCR recruits the tyrosine kinase ZAP70, that becomes phosphorylated and activated by LCK. Following this, a large number of signaling molecules are recruited, ultimately leading to lymphokine production. LCK also contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, which leads to hyperphosphorylation and activation of LCK. Also plays a role in the IL2 receptor-linked signaling pathway that controls the T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. Phosphorylates other substrates including RUNX3, PTK2B/PYK2, the microtubule-associated protein MAPT, RHOH or TYROBP. Interacts with FYB2 (PubMed:27335501)
Specific Function: ATP binding
Gene Name: LCK
Uniprot ID: P06239
Uniprot Name: Tyrosine-protein kinase Lck
Molecular Weight: 58000.15 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details11. Tyrosine-protein kinase Lyn

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Involved in the regulation of endothelial activation, neutrophil adhesion and transendothelial migration (PubMed:36932076). Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138)
Specific Function: ATP binding
Gene Name: LYN
Uniprot ID: P07948
Uniprot Name: Tyrosine-protein kinase Lyn
Molecular Weight: 58573.595 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details12. Proto-oncogene tyrosine-protein kinase Src

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Phosphorylates PKP3 at 'Tyr-195' in response to reactive oxygen species, which may cause the release of PKP3 from desmosome cell junctions into the cytoplasm (PubMed:25501895). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:14585963, PubMed:8755529). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances RIGI-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Phosphorylates synaptic vesicle protein synaptophysin (SYP) (By similarity). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159). Phosphorylates OTUB1, promoting deubiquitination of RPTOR (PubMed:35927303). Phosphorylates caspase CASP8 at 'Tyr-380' which negatively regulates CASP8 processing and activation, down-regulating CASP8 proapoptotic function (PubMed:16619028)
Specific Function: ATP binding
Gene Name: SRC
Uniprot ID: P12931
Uniprot Name: Proto-oncogene tyrosine-protein kinase Src
Molecular Weight: 59834.295 Da

References

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ: BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82. doi: 10.1158/0008-5472.CAN-07-6307. [Article]
Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Enzymes

Details1. UDP-glucuronosyltransferase 1A1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
Specific Function: enzyme binding
Gene Name: UGT1A1
Uniprot ID: P22309
Uniprot Name: UDP-glucuronosyltransferase 1A1
Molecular Weight: 59590.91 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details2. UDP-glucuronosyltransferase 1A7

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15470161, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:20610558, PubMed:23360619). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormone epiestradiol (PubMed:18719240). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558, PubMed:23360619). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161)
Specific Function: enzyme binding
Gene Name: UGT1A7
Uniprot ID: Q9HAW7
Uniprot Name: UDP-glucuronosyltransferase 1A7
Molecular Weight: 59818.315 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details3. UDP-glucuronosyltransferase 1A8

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:15472229, PubMed:16595710, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:15472229, PubMed:16595710, PubMed:23288867). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens and estrogens (PubMed:15472229, PubMed:16595710, PubMed:18719240, PubMed:23288867). Produces dihydrotestosterone (DHT) diglucuronide from the DHT after two subsequent glucoronidation steps (PubMed:16595710). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
Specific Function: enzyme binding
Gene Name: UGT1A8
Uniprot ID: Q9HAW9
Uniprot Name: UDP-glucuronosyltransferase 1A8
Molecular Weight: 59741.035 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details4. UDP-glucuronosyltransferase 1A10

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:18719240, PubMed:19545173, PubMed:23288867, PubMed:26220143). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:18719240, PubMed:23288867, PubMed:26220143). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II (PubMed:18674515)
Specific Function: enzyme binding
Gene Name: UGT1A10
Uniprot ID: Q9HAW8
Uniprot Name: UDP-glucuronosyltransferase 1A10
Molecular Weight: 59809.075 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details5. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Carriers

Details1. Albumin

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function: antioxidant activity
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Albumin
Molecular Weight: 69365.94 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]

Transporters

Details1. ATP-dependent translocase ABCB1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]
FDA Approved Drug Products: Ofev (nintedanib) capsules for oral use [Link]

Details2. Solute carrier family 22 member 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930)
Specific Function: (R)-carnitine transmembrane transporter activity
Gene Name: SLC22A1
Uniprot ID: O15245
Uniprot Name: Solute carrier family 22 member 1
Molecular Weight: 61153.345 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]

Details3. Broad substrate specificity ATP-binding cassette transporter ABCG2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: Broad substrate specificity ATP-binding cassette transporter ABCG2
Molecular Weight: 72313.47 Da

References

Wind S, Schmid U, Freiwald M, Marzin K, Lotz R, Ebner T, Stopfer P, Dallinger C: Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib. Clin Pharmacokinet. 2019 Sep;58(9):1131-1147. doi: 10.1007/s40262-019-00766-0. [Article]

Drug created at June 24, 2015 11:32 / Updated at November 06, 2024 20:01

Nintedanib

Overview

Identification

Structure for Nintedanib (DB09079)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

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Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

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Enzymes

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Carriers

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Transporters

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