Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97.

ABSTRACT: 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.

SUBMITTER: LaPorte MG 

PROVIDER: S-EPMC6231190 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature