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Accelerating inhibitor discovery for deubiquitinating enzymes.

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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.

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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.