Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer

Matthew G. LaPorte, Celeste Alverez, Alexander Chatterley, Marina Kovaliov, Evan J. Carder, Michael J. Houghton, Chaemin Lim, Eric R. Miller, Lalith P. Samankumara, Mary Liang, Kaylan Kerrigan, Zhizhou Yue, Shan Li, Francesca Tomaino, Feng Wang, Neal Green, Gordon M. Stott, Apurva Srivastava, Tsui Fen Chou, Peter WipfDonna M. Huryn

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The AAA+ ATPase p97 (valosin-containing protein, VCP) is a master regulator of protein homeostasis and therefore represents a novel target for cancer therapy. Starting from a known allosteric inhibitor, NMS-873, we systematically optimized this scaffold, in particular, by applying a benzene-to-acetylene isosteric replacement strategy, specific incorporation of F, and eutomer/distomer identification, which led to compounds that exhibited nanomolar biochemical and cell-based potency. In cellular pharmacodynamic assays, robust effects on biomarkers of p97 inhibition and apoptosis, including increased levels of ubiquitinated proteins, CHOP and cleaved caspase 3, were observed. Compound (R)-29 (UPCDC-30766) represents the most potent allosteric inhibitor of p97 reported to date.

Original languageEnglish
Pages (from-to)977-985
Number of pages9
JournalACS Medicinal Chemistry Letters
Issue number7
StatePublished - 13 Jul 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society


  • AAA+ ATPase
  • NMS-873
  • allosteric inhibitor
  • anticancer
  • benzene isostere
  • p97
  • protein homeostasis modulator
  • valosin-containing protein


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