2. Academic Validation
  3. Discovery of small-molecule inhibitors of RUVBL1/2 ATPase

Discovery of small-molecule inhibitors of RUVBL1/2 ATPase

  • Bioorg Med Chem. 2022 May 15;62:116726. doi: 10.1016/j.bmc.2022.116726.
Gang Zhang 1,  Feng Wang 2,  Shan Li 2,  Kai-Wen Cheng 2,  Yingying Zhu 3,  Ran Huo 3,  Elyar Abdukirim 3,  Guifeng Kang 4,  Tsui-Fen Chou 5
Affiliations

Affiliations

  • 1 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States. Electronic address: gzhang2@caltech.edu.
  • 2 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States.
  • 3 School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
  • 4 School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: guifengkang@ccmu.edu.cn.
  • 5 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States; Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, United States. Electronic address: tfchou@caltech.edu.
PMID: 35364523 DOI: 10.1016/j.bmc.2022.116726
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.

Keywords

AAA ATPase; Docking; Organic synthesis; Pontin; Proteomics; Pyrazolo[1,5-a]pyrimidine-3-carboxamide; RUVBL1; RUVBL2, Reptin.

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