Accelerating inhibitor discovery for deubiquitinating enzymes
Wai Cheung Chan1,2, Xiaoxi Liu1,2, Robert S Magin1,2
1Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature Communications
|February 8, 2023
Summary
Researchers developed a targeted chemical library to find selective probes for deubiquitinating enzymes (DUBs). This approach successfully identified probes for 23 DUBs, including a potent probe for VCPIP1, advancing DUB-targeted drug discovery.
Area of Science:
- Biochemistry
- Chemical Biology
- Drug Discovery
Background:
- Deubiquitinating enzymes (DUBs) are crucial proteases regulating cellular processes by cleaving ubiquitin.
- A scarcity of selective chemical probes hinders the pharmacologic study of DUBs.
- DUBs interact with substrates through diverse binding mechanisms.
Purpose of the Study:
- To develop a chemical diversification strategy for a DUB-focused covalent library.
- To identify selective chemical probes for DUBs using activity-based protein profiling.
- To optimize identified hits into potent and selective DUB inhibitors.
Main Methods:
- Designed and synthesized a purpose-built covalent chemical library targeting DUBs.
- Employed activity-based protein profiling (ABPP) for high-density screening.
- Performed structure-activity relationship (SAR) studies for hit optimization.
Main Results:
- Identified selective hits against 23 endogenous DUBs across four subfamilies.
- Developed a potent nanomolar probe for the understudied DUB VCPIP1 with in-family selectivity.
- Established structure-activity relationships for DUB inhibitors from a focused library.
Conclusions:
- A tailored, modest chemical library coupled with ABPP is effective for discovering selective DUB probes.
- This strategy challenges the emphasis on ultrahigh-throughput screening for DUB-focused drug discovery.
- The identified probes and SAR provide valuable starting points for further DUB-targeted therapeutic development.
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