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Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97
- 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
Published Web Location
https://doi.org/10.1021/acsmedchemlett.8b00372Abstract
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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