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Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

Matthew G LaPorte¹, James C Burnett^1,2, Raffaele Colombo¹

¹University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

ACS Medicinal Chemistry Letters

|November 16, 2018

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.

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