Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excel...

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Bibliographic Details
Published in:ACS medicinal chemistry letters Vol. 9; no. 11; pp. 1075 - 1081
Main Authors: LaPorte, Matthew G, Burnett, James C, Colombo, Raffaele, Bulfer, Stacie L, Alverez, Celeste, Chou, Tsui-Fen, Neitz, R. Jeffrey, Green, Neal, Moore, William J, Yue, Zhizhou, Li, Shan, Arkin, Michelle R, Wipf, Peter, Huryn, Donna M
Format: Journal Article
Language:English
Published: United States American Chemical Society 08-11-2018
Subjects:
protein homeostasis modulator
allosteric inhibitor
phenyl indole
AAA+ ATPase
anticancer
p97
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Summary:Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00372