Novel Hsp90-Targeting PROTACs: Enhanced synergy with cisplatin in combination therapy of cervical cancer.

Autor: Liang J; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Wang D; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Zhao Y; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Wu Y; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Liu X; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Xin L; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Dai J; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Ren H; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China., Zhou HB; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University, Wuhan, 430071, China., Cai H; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: chb2105@163.com., Dong C; Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University, Wuhan, 430071, China. Electronic address: cdong@whu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116572. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1016/j.ejmech.2024.116572
Abstrakt: The development of effective drugs for cervical cancer is urgently required because of its high mortality rate and the limited treatment options. Herein, we report the design, synthesis, and evaluation of a series of novel and effective Hsp90-targeting PROTACs. These compounds exhibited potent anti-proliferative activity against cervical cancer cells with low IC 50 values. Compound lw13 effectively degraded Hsp90 at a concentration of only 0.05 μM. In addition, it can inhibit the metastasis of cancer cells and induce significant cell cycle arrest and apoptosis. Furthermore, lw13 demonstrated remarkable antitumor activity both in vitro and in vivo, and has a synergistic effect in combination with cisplatin. Moreover, lw13 can prevent the activation of the HER2/AKT/mTOR signaling pathway by indirectly reducing the levels of HER2 and AKT. This study paves the way for cancer treatment and provides valuable insights into the combination therapy of cervical cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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