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

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.

SUBMITTER: Alverez C

PROVIDER: S-EPMC4753542 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Alverez Celeste C Bulfer Stacie L SL Chakrasali Ramappa R Chimenti Michael S MS Deshaies Raymond J RJ Green Neal N Kelly Mark M LaPorte Matthew G MG Lewis Taber S TS Liang Mary M Moore William J WJ Neitz R Jeffrey RJ Peshkov Vsevolod A VA Walters Michael A MA Zhang Feng F Arkin Michelle R MR Wipf Peter P Huryn Donna M DM

ACS medicinal chemistry letters 20151222 2

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. ...[more]

PMID: 26985295

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