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

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

  • Eur J Med Chem. 2024 Sep 5:275:116572. doi: 10.1016/j.ejmech.2024.116572.
Jinsen Liang 1,  Dandan Wang 1,  Yijin Zhao 1,  Yihe Wu 1,  Xuelian Liu 1,  Lilan Xin 1,  Junhong Dai 1,  Hang Ren 1,  Hai-Bing Zhou 2,  Hongbing Cai 3,  Chune Dong 4
Affiliations

Affiliations

  • 1 Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 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.
  • 3 Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: chb2105@163.com.
  • 4 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.
PMID: 38861809 DOI: 10.1016/j.ejmech.2024.116572
Abstract

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 IC50 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.

Keywords

Cervical cancer; Degradation; Drug combination; Hsp90; PROTACs.

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