1. Novel Hsp90-Targeting PROTACs: Enhanced synergy with cisplatin in combination therapy of cervical cancer.
- Author
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Liang J, Wang D, Zhao Y, Wu Y, Liu X, Xin L, Dai J, Ren H, Zhou HB, Cai H, and Dong C
- Subjects
- Humans, Female, Drug Synergism, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Animals, Cell Line, Tumor, Mice, Proteolysis Targeting Chimera, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms metabolism, Cisplatin pharmacology, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins metabolism, Cell Proliferation drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Apoptosis drug effects, Drug Screening Assays, Antitumor
- 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 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.)- Published
- 2024
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