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Review
. 2023 Jul 27;4(9):623-634.
doi: 10.1039/d3cb00105a. eCollection 2023 Aug 30.

PROTAC chemical probes for histone deacetylase enzymes

Urvashi Patel  1 , Joshua P Smalley  1 , James T Hodgkinson  1
Affiliations
Review

PROTAC chemical probes for histone deacetylase enzymes

Urvashi Patel et al. RSC Chem Biol. .

Abstract

Over the past three decades, we have witnessed the progression of small molecule chemical probes designed to inhibit the catalytic active site of histone deacetylase (HDAC) enzymes into FDA approved drugs. However, it is only in the past five years we have witnessed the emergence of proteolysis targeting chimeras (PROTACs) capable of promoting the proteasome mediated degradation of HDACs. This is a field still in its infancy, however given the current progress of PROTACs in clinical trials and the fact that FDA approved HDAC drugs are already in the clinic, there is significant potential in developing PROTACs to target HDACs as therapeutics. Beyond therapeutics, PROTACs also serve important applications as chemical probes to interrogate fundamental biology related to HDACs via their unique degradation mode of action. In this review, we highlight some of the key findings to date in the discovery of PROTACs targeting HDACs by HDAC class and HDAC isoenzyme, current gaps in PROTACs to target HDACs and future outlooks.

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Conflict of interest statement

J. T. H. and J. P. S. are inventors on the PCT patent application WO2021148811A1 and the following patents: JP2023-510947, US2023-0120211A1.

Figures

Fig. 1
Fig. 1. Top: Vorinostat, romidepsin, belinostat and panobinostat are drugs that inhibit the HDAC catalytic active site and are FDA approved. Tucidinostat has been approved for in-patient use in China. Bottom: Crystal structure of HDAC2 with vorinostat bound via the hydroxamic acid functional group to Zn2+ in the HDAC catalytic active site PDB: 4LXZ.
Fig. 2
Fig. 2. Example of how the pan-kinase inhibitor foretinib can be transformed into a selective kinase protein degrader.
Chart 1
Chart 1. PROTAC 3 degrades HDAC1 at a concentration of 10 μM, but also effectively degrades HDAC6 at 1 μM in HL-60 cells.4 and 5 degrade HDAC1 with DC50 values of 0.55 μM and 0.91 μM respectively in HCT-116 cells and degrade HDAC2,5 exhibits a DC50 value of 4.19 μM for HDAC2. HDAC3 is degraded with 4 and 5 with DC50 values of 0.53 μM and 0.64 μM respectively, however a hook effect is observed for HDAC3 at concentrations >1 μM which is not observed for HDAC1 and HDAC2. 6 degrades HDAC1 with a DC50 value of 2.8 μM and also degrades HDAC2 and HDAC3, 6 exhibits a similar hook effect with HDAC3 at concentrations >2.5 μM.
Chart 2
Chart 2. PROTACs reported for the selective degradation of HDAC3. 7 HDAC3 DC50 = 42 nM and 7 exhibits selectivity over HDAC1, HDAC2 and HDAC6 in MDA-MB-468 cells.8 HDAC3 DC50 = 0.32 μM in RAW 264.7 macrophages.9 and 10 were identified in a proteomics study by Xiong et al. with selectivity for HDAC3 degradation in KELLY cells, however this HDAC3 selectivity was completely compromised in MM.1S cells.11 HDAC3 DC50 = 0.44 μM and exhibits selectivity over HDAC1 and HDAC2 in HCT116 cells.
Chart 3
Chart 3. PROTACs reported for the selective degradation of HDAC8. 12 HDAC8 DC50 = 0.7 μM in jurkat cells.13 HDAC8 DC50 = 147 nM and HDAC6 DC50 = 4.95 μM in HCT-116 cells.14 degrades HDAC8 with a Dmax value of 70% at 10 μM in SK-N-BE(2)-C neuroblastoma cells.15 HDAC8 DC50 = 0.58 μM in A549 cells.16 HDAC8 DC50 = 1.8 nM and HDAC6 DC50 value = 38 nM in MDA-MB-231 cells.16 HDAC8 DC50 = 4.7 nM and HDAC6 DC50 = 78.5 nM in jurkat cells.
Chart 4
Chart 4. PROTACs reported for the selective degradation of HDAC4. PROTAC 17 DC50 = 37 nM and Dmax value of 83% in Jurkat E6-1 cells. PROTAC 18 DC50 = 4 nM and Dmax value of 78% in Jurkat E6-1 cells. PROTAC 17 exhibits a hook effect with HDAC4 at 10 μM in Jurkat E6-1 cells.
Chart 5
Chart 5. PROTACs reported for the selective degradation of HDAC6. 19 HDAC6 DC50 = 34 nM in MCF-7 cells;20 HDAC6 DC50 = 3.8 nM in MM.1S cells;21 HDAC6 DC50 = 1.6 nM in MM.1S cells and also degrades IKZF1/3;22 degrades HDAC6 > 50% at 10 nM;23 HDAC6 DC50 = 3.2 nM in MM.1S cells;24 HDAC6 DC50 = 7.1 nM in MM.1S cells;25 HDAC6 DC50 = 108.9 nM in K562 cells;26 and 27 exhibit DC50 values of 3.5 nM and 19.4 nM respectively for HDAC6 in HL-60 cells.28 and 29 exhibit DC50 values of 131 nM and 171 nM for HDAC6 respectively in MM.1S cells.
Chart 6
Chart 6. PROTACs reported for the selective degradation of SIRT2. 30 degrades SIRT2 selectively over SIRT 1 at a concertation range of 0.2–10 μM in HeLa cells.31 and 32 degrade SIRT2 at concentration range of 0.5–10 μM in MCF7 and BT-549 cells with no SIRT1 degradation observed.
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