Login / Signup

Accelerating inhibitor discovery for deubiquitinating enzymes.

Wai Cheung ChanXiaoxi LiuRobert S MaginNicholas M GirardiScott B FicarroWanyi HuMaria I Tarazona GuzmanCara A StarnbachAlejandra FelixGuillaume AdelmantAnthony C VarcaBin HuAriana S BrattEthan DaSilvaNathan J SchauerIsabella Jaen MaisonetEmma K DolenAnthony X AyalaJarrod A MartoSara J Buhrlage
Published in: Nature communications (2023)
Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack of selective chemical probes impedes pharmacologic interrogation of this important gene family. DUBs engage their cognate ligands through a myriad of interactions. We embrace this structural complexity to tailor a chemical diversification strategy for a DUB-focused covalent library. Pairing our library with activity-based protein profiling as a high-density primary screen, we identify selective hits against 23 endogenous DUBs spanning four subfamilies. Optimization of an azetidine hit yields a probe for the understudied DUB VCPIP1 with nanomolar potency and in-family selectivity. Our success in identifying good chemical starting points as well as structure-activity relationships across the gene family from a modest but purpose-build library challenges current paradigms that emphasize ultrahigh throughput in vitro or virtual screens against an ever-increasing scope of chemical space.
Keyphrases
  • high density
  • small molecule
  • high throughput
  • protein protein
  • living cells
  • amino acid
  • genome wide
  • gene expression
  • electronic health record
  • heat stress
  • genome wide analysis