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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8
Zhiqiang Sun1, Bulian Deng1, Zichao Yang1
1School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
Abstract:
Overexpression of histone deacetylase 8 (HDAC8) is associated with various diseases such as cancer. Thus, compounds that can modulate HDAC8 levels have therapeutic potential for these diseases. Based on the proteolysis targeting chimera (PROTAC) strategy, we designed and synthesized a series of HDAC8 degraders by tethering an HDAC6/8 dual inhibitor with pomalidomide (a cereblon ligand). Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 with DC50 of 147 nM and Dmax of 93%, and exhibited no effects on HDAC1 and HDAC3. Interestingly, we found that the degradation of target protein started at ∼2 h after treatment with ZQ-23 and the maximal degradation effect was achieved at 10 h. The HDAC8 level was partially recovered within 24 h. In addition, ZQ-23 had no degrading effects on HDAC1 and HDAC3 at all concentrations, but could dose-dependently increase the levels of acetylated SMC-3 (HDAC8 substrate). Mechanism study demonstrated that ZQ-23 degraded HDAC8 through the ubiquitin-protease pathway, rather than lysosome system. Collectively, these results suggest that ZQ-23 represents a novel PROTAC-based HDAC8 degrader worthy of further investigation.
Insights
Researchers developed a novel PROTAC degrader, ZQ-23, to target histone deacetylase 8 (HDAC8) overexpression linked to diseases like cancer. This compound selectively degrades HDAC8, showing therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Histone deacetylase 8 (HDAC8) overexpression is implicated in various diseases, including cancer.
- Targeting HDAC8 offers therapeutic potential for disease treatment.
Purpose of the Study:
- To design and synthesize novel proteolysis targeting chimera (PROTAC) molecules targeting HDAC8.
- To evaluate the efficacy and selectivity of synthesized compounds as HDAC8 degraders.
Main Methods:
- Utilized PROTAC strategy by conjugating an HDAC6/8 dual inhibitor with pomalidomide.
- Synthesized and screened a series of HDAC8 degraders.
- Assessed compound selectivity, degradation kinetics, and mechanism of action.
Main Results:
- Compound ZQ-23 demonstrated potent and selective HDAC8 degradation (DC50 = 147 nM, Dmax = 93%) without affecting HDAC1 or HDAC3.
- HDAC8 degradation initiated within 2 hours, peaked at 10 hours, with partial recovery within 24 hours.
- ZQ-23 increased acetylated SMC-3 levels and degraded HDAC8 via the ubiquitin-proteasome pathway.
Conclusions:
- ZQ-23 is a novel PROTAC-based HDAC8 degrader with significant potential for further investigation.
- Selective HDAC8 degradation offers a promising therapeutic strategy for HDAC8-associated diseases.
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