Open AccessOptimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
Author(s) -
Matthew G. LaPorte,
James C. Burnett,
Raffaele Colombo,
Stacie L. Bulfer,
Celeste Alverez,
TsuiFen Chou,
R. Jeffrey Neitz,
Neal Green,
William Moore,
Zhizhou Yue,
Shan Li,
Michelle R. Arkin,
Peter Wipf,
Donna M. Huryn
Publication year - 2018
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.8b00372
Subject(s) - indole test , potency , allosteric regulation , piperazine , chemistry , atpase , alkyl , stereochemistry , pharmacology , combinatorial chemistry , biochemistry , computational biology , in vitro , enzyme , biology , organic chemistry
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.
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