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 Wipf; Donna M. Huryn

doi:10.1021/acsmedchemlett.3c00163

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 journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	977-985
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	14
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.3c00163
State	Published - 13 Jul 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society

Funding

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. 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.

Funders	Funder number
Barbara Mroczkowski
National Institutes of Health	HHSN261200800001E, 29XS127TO15
National Cancer Institute

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.3c00163

Cite this

LaPorte, M. G., Alverez, C., Chatterley, A., Kovaliov, M., Carder, E. J., Houghton, M. J., Lim, C., Miller, E. R., Samankumara, L. P., Liang, M., Kerrigan, K., Yue, Z., Li, S., Tomaino, F., Wang, F., Green, N., Stott, G. M., Srivastava, A., Chou, T. F., ... Huryn, D. M. (2023). Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer. ACS Medicinal Chemistry Letters, 14(7), 977-985. https://doi.org/10.1021/acsmedchemlett.3c00163

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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.",

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year = "2023",

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doi = "10.1021/acsmedchemlett.3c00163",

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LaPorte, MG, Alverez, C, Chatterley, A, Kovaliov, M, Carder, EJ, Houghton, MJ, Lim, C, Miller, ER, Samankumara, LP, Liang, M, Kerrigan, K, Yue, Z, Li, S, Tomaino, F, Wang, F, Green, N, Stott, GM, Srivastava, A, Chou, TF, Wipf, P & Huryn, DM 2023, 'Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer', ACS Medicinal Chemistry Letters, vol. 14, no. 7, pp. 977-985. https://doi.org/10.1021/acsmedchemlett.3c00163

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T1 - Optimization of 1,2,4-Triazole-Based p97 Inhibitors for the Treatment of Cancer

AU - LaPorte, Matthew G.

AU - Alverez, Celeste

AU - Chatterley, Alexander

AU - Kovaliov, Marina

AU - Carder, Evan J.

AU - Houghton, Michael J.

AU - Lim, Chaemin

AU - Miller, Eric R.

AU - Samankumara, Lalith P.

AU - Liang, Mary

AU - Kerrigan, Kaylan

AU - Yue, Zhizhou

AU - Li, Shan

AU - Tomaino, Francesca

AU - Wang, Feng

AU - Green, Neal

AU - Stott, Gordon M.

AU - Srivastava, Apurva

AU - Chou, Tsui Fen

AU - Wipf, Peter

AU - Huryn, Donna M.

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AB - 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.

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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