2. Academic Validation
  3. Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification

Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification

  • Cell Chem Biol. 2021 Oct 21;28(10):1446-1459.e6. doi: 10.1016/j.chembiol.2021.03.016.
Li Li 1,  Nannan Chen 1,  Dandan Xia 2,  Shicheng Xu 1,  Wei Dai 1,  Yuanyuan Tong 1,  Lei Wang 1,  Zhengyu Jiang 3,  Qidong You 4,  Xiaoli Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 3 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jiangzhengyucpu@163.com.
  • 4 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
  • 5 State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xuxiao_li@126.com.
PMID: 33932325 DOI: 10.1016/j.chembiol.2021.03.016
Abstract

Heat shock protein (HSP90), a critical molecular chaperone that regulates the maturation of a large number of oncogenic client proteins, plays an essential role in the growth of neoplastic cells. Herein, DDO-6600 is identified to covalent modification of Cys598 on HSP90 from in silico study and is verified by a series of biological assays. We demonstrated that DDO-6600 covalently bound to Cys598 on the HSP90 C terminus and exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity. Further studies showed that DDO-6600 disrupted the interaction between HSP90 and Cdc37, which induced the degradation of kinase client proteins in multiple tumor cell lines, promoted Apoptosis, and inhibited cell motility. Our findings offer mechanic insights into the covalent modification of HSP90 and provide an alternative strategy for the development of HSP90 covalent regulators or chemical probes to explore the therapeutical potential of HSP90.

Keywords

antitumor; chemical biology; co-chaperones; computational screening; cysteines; degradation of client proteins; heat shock protein 90.

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