Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer
- Creators
- LaPorte, Matthew G.
- Alverez, Celeste
- Chatterley, Alexander
- Kovaliov, Marina
- Carder, Evan J.
- Houghton, Michael J.
- Lim, Chaemin
- Miller, Eric R.
- Samankumara, Lalith P.
- Liang, Mary
- Kerrigan, Kaylan
- Yue, Zhizhou
- Li, Shan
- Tomaino, Francesca
- Wang, Feng
- Green, Neal
- Stott, Gordon M.
- Srivastava, Apurva
- Chou, Tsui-Fen
- Wipf, Peter
- Huryn, Donna M.
Abstract
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.
Additional Information
© 2023 American Chemical Society. The authors gratefully acknowledge James Burnett, Desirae Crocker, Alyssa Thornton, and Taber Maskrey (Pitt) for experimental contributions, William Moore and John Giraldes (Leidos), Barbara Mroczkowski (NCI), Mark Wolf and Bill Paquette (AMRI, Curia), Raymond Deshaies (CalTech), and Michelle Arkin (UCSF) for helpful discussions, Andrew Flint (Leidos) for helpful discussions and review of the manuscript, AMRI/Curia for chiral separation and scale-up of intermediates, and Robert Suto and XtalBiostructures for preliminary SPR data. The project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Chemical Biology Consortium Contract No. HHSN261200800001E, Agreement No. 29XS127TO15. Author Contributions: The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interest.Attached Files
Supplemental Material - ml3c00163_si_001.pdf
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Additional details
- PMCID
- PMC10351062
- Eprint ID
- 122241
- Resolver ID
- CaltechAUTHORS:20230711-988768900.15
- HHSN261200800001E
- NIH
- 29XS127TO15
- NIH
- Created
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2023-08-11Created from EPrint's datestamp field
- Updated
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2023-08-14Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering