2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells

Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells

  • Eur J Med Chem. 2022 Nov 15;242:114674. doi: 10.1016/j.ejmech.2022.114674.
Zhaoping Pan 1,  Yi Chen 2,  Haiying Pang 1,  Xiaoyun Wang 1,  Yuehua Zhang 1,  Xin Xie 3,  Gu He 4
Affiliations

Affiliations

  • 1 Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 3 College of Medical Technology and School of Pharmacy, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. Electronic address: xiexin@cdutcm.edu.cn.
  • 4 Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address: hegu@scu.edu.cn.
PMID: 35987020 DOI: 10.1016/j.ejmech.2022.114674
Abstract

In this study, a novel class of thieno [2,3-d] pyrimidine derivatives containing resorcinol and morpholine fragments as HSP90/mTOR dual inhibitors was designed, synthesized, and evaluated. In vitro anti-tumor assay results: the obtained compounds demonstrated effectiveness in suppressing the enzymatic activities of the HSP90 and mTOR and inhibiting the proliferation of J82, T24, and SW780 Cancer cell lines. Among these dual inhibitors, the most potent compound 17o, confirmed remarkable inhibitory activities on HSP90, mTOR, and SW780 cell. Furthermore, the molecular dynamics simulation and a panel of mechanism studies revealed that inhibitor 17o suppressed the proliferation of SW780 cells through the over-activation of the PI3K/Akt/mTOR pathway regulated by mTOR inhibition and Apoptosis regulated by the mitochondrial pathway. In subcutaneous J82 xenograft models, the compound 17o also presented considerable in vivo anti-tumor activity. Therefore, our investigations highlight that a new-found dual HSP90/mTOR Inhibitor by rational drug design strategies could be a promising lead compound for targeted bladder Cancer therapy and deserves further studies.

Keywords

Autophagy; Bladder cancer; Dual inhibitor; Hsp90; mTOR.

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