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

  • Author(s): 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
  • et al.
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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