Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway

Celeste Alverez, Stacie L. Bulfer, Ramappa Chakrasali, Michael S. Chimenti, Raymond J. Deshaies, Neal Green, Mark Kelly, Matthew G. LaPorte, Taber S. Lewis, Mary Liang, William J. Moore, R. Jeffrey Neitz, Vsevolod A. Peshkov, Michael A. Walters, Feng Zhang, Michelle R. Arkin, Peter Wipf, Donna M. Huryn

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts.

Original languageEnglish
Pages (from-to)182-187
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 11 2016
Externally publishedYes

Keywords

  • AAA ATPase
  • allosteric inhibitor
  • indole amide
  • p97 inhibitor
  • protein homeostasis
  • ubiquitin pathway modulator

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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