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Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy

Wang, Feng and Li, Shan and Gan, Taiping and Stott, Gordon M. and Flint, Andrew J. and Chou, Tsui-Fen (2020) Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy. ChemMedChem, 15 (8). pp. 685-694. ISSN 1860-7179. PMCID PMC9049325. doi:10.1002/cmdc.201900722.

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A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is a central regulator of protein homeostasis and a promising anti‐cancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells treated with CB‐5083 identified 5 different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660K and T688A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649A/T688A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent than CB‐5083 in inhibiting the CB‐5083 resistant D649A/T688A double mutant. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anti‐cancer treatment.

Item Type:Article
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URLURL TypeDescription CentralArticle
Li, Shan0000-0002-0829-1821
Stott, Gordon M.0000-0002-9148-6100
Chou, Tsui-Fen0000-0003-2410-2186
Alternate Title:Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy
Additional Information:© 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Accepted manuscript online: 11 March 2020; Manuscript accepted: 05 March 2020; Manuscript revised: 15 February 2020; Manuscript received: 21 December 2019. We thank the University of Kansas Specialized Chemistry Center for providing DeBQ, ML240, ML241 and University of Pittsburgh Chemical Diversity Center for providing UPCDC-30245. We thank Jingying Xu for helping on maintaining the CB-5083 resistant line, Xiaoyi Zhang and Lin Gui for assistance with preparing samples to determine intracellular compound concentration, and Paul Sternberg for editorial suggestions. We thank Quintara Discovery for LC-MS/MS analysis. We thank Neal Green for helpful suggestion. The project was supported in part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E, through the NExT Chemical Biology Consortium.
Funding AgencyGrant Number
Subject Keywords:p97 VCP; resistance; small molecule inhibitor; ATPase; cancer
Issue or Number:8
PubMed Central ID:PMC9049325
Record Number:CaltechAUTHORS:20200316-130434745
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Official Citation:Allosteric p97 inhibitors can overcome resistance to ATP-competitive p97 inhibitors for potential anti-cancer therapy. F. Wang., S. Li, T. Gan, G. M. Stott, A. Flint, T.-F. Chou, ChemMedChem 2020, 15, 685. doi: 10.1002/cmdc.201900722
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101920
Deposited By: Tony Diaz
Deposited On:16 Mar 2020 22:13
Last Modified:10 May 2022 16:16

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