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

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...

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Bibliographic Details
Published inACS medicinal chemistry letters Vol. 7; no. 2; pp. 182 - 187
Main Authors Alverez, Celeste, Bulfer, Stacie L, Chakrasali, Ramappa, Chimenti, Michael. S, Deshaies, Raymond J, Green, Neal, Kelly, Mark, LaPorte, Matthew G, Lewis, Taber S, Liang, Mary, Moore, William J, Neitz, R. Jeffrey, Peshkov, Vsevolod A, Walters, Michael A, Zhang, Feng, Arkin, Michelle R, Wipf, Peter, Huryn, Donna M
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 11.02.2016
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
indole amide
ubiquitin pathway modulator
allosteric inhibitor
p97 inhibitor
protein homeostasis
AAA ATPase
SYSTEM
VALOSINE
AAA ATPASE P97
PROTEIN
CHAPERONE P97
CANCER
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00396