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Discovery of small-molecule inhibitors of RUVBL1/2 ATPase

Zhang, Gang and Wang, Feng and Li, Shan and Cheng, Kai-Wen and Zhu, Yingying and Huo, Ran and Abdukirim, Elyar and Kang, Guifeng and Chou, Tsui-Fen (2022) Discovery of small-molecule inhibitors of RUVBL1/2 ATPase. Bioorganic and Medicinal Chemistry, 62 . Art. No. 116726. ISSN 0968-0896. PMCID PMC9034851. doi:10.1016/j.bmc.2022.116726. https://resolver.caltech.edu/CaltechAUTHORS:20220329-753949840

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Abstract

RUVBL1 and RUVBL2 are highly conserved AAA ATPases (ATPases Associated with various cellular Activities) and highly relevant to the progression of cancer, which makes them attractive targets for novel therapeutic anticancer drugs. In this work, docking-based virtual screening was performed to identify compounds with activity against the RUVBL1/2 complex. Seven compounds showed inhibitory activity against the complex in both enzymatic and cellular assays. A series of pyrazolo[1,5-a]pyrimidine-3-carboxamide analogs were synthesized based on the scaffold of compound 15 with inhibitory activity and good potential for structural manipulation. Analysis of the structure–activity relationship identified the benzyl group on R₂ and aromatic ring-substituted piperazinyl on R₄ as essential for inhibitory activity against the RUVBL1/2 complex. Of these, compound 18, which has IC₅₀ values of 6.0 ± 0.6 μM and 7.7 ± 0.9 μM against RUVBL1/2 complex and RUVBL1 respectively, showed the most potent inhibition in cell lines A549, H1795, HCT116, and MDA-MB-231 with IC₅₀ values of 15 ± 1.2 μM, 15 ± 1.8 μM, 11 ± 1.0 μM, and 8.9 ± 0.9 μM respectively. A docking study of the compound was performed to predict the binding mode of pyrazolo[1,5-a]pyrimidine-3-carboxamides. Furthermore, mass spectrometry-based proteomic analysis was employed to explore cellular proteins dysregulated by treatment with compounds 16, 18, and 19. Together, the data from these analyses suggest that that compound 18 could serve as a starting point for structural modifications in order to improve potency, selectivity, and pharmacokinetic parameters of potential therapeutic molecules.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.bmc.2022.116726DOIArticle
ORCID:
AuthorORCID
Zhang, Gang0000-0003-0774-5710
Li, Shan0000-0002-0829-1821
Cheng, Kai-Wen0000-0001-9888-9773
Chou, Tsui-Fen0000-0003-2410-2186
Additional Information:© 2022 Elsevier. Received 25 January 2022, Revised 7 March 2022, Accepted 22 March 2022, Available online 26 March 2022, Version of Record 29 March 2022. This work was supported in part by the National Institute of Child Health and Human Development R01 HD086596 and The Cultivation Fund of School of Pharmaceutical Sciences, Capital Medical University (2021).
Funders:
Funding AgencyGrant Number
NIHR01 HD086596
Capital Medical UniversityUNSPECIFIED
Subject Keywords:RUVBL1; Pontin; RUVBL2, Reptin; AAA ATPase; Organic synthesis; Docking; Pyrazolo[1,5-a]pyrimidine-3-carboxamide; Proteomics
PubMed Central ID:PMC9034851
DOI:10.1016/j.bmc.2022.116726
Record Number:CaltechAUTHORS:20220329-753949840
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220329-753949840
Official Citation:Gang Zhang, Feng Wang, Shan Li, Kai-Wen Cheng, Yingying Zhu, Ran Huo, Elyar Abdukirim, Guifeng Kang, Tsui-Fen Chou, Discovery of small-molecule inhibitors of RUVBL1/2 ATPase, Bioorganic & Medicinal Chemistry, Volume 62, 2022, 116726, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2022.116726.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114116
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:29 Mar 2022 12:27
Last Modified:25 Jul 2022 23:14

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  • Zhang, Gang and Wang, Feng and Li, Shan and Cheng, Kai-Wen and Zhu, Yingying and Huo, Ran and Abdukirim, Elyar and Kang, Guifeng and Chou, Tsui-Fen Discovery of small-molecule inhibitors of RUVBL1/2 ATPase. (deposited 29 Mar 2022 12:27) [Currently Displayed]

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