Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
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.
Eur J Med Chem. 2024 Sep 5;275:116572. doi: 10.1016/j.ejmech.2024.116572. Epub 2024 Jun 6.
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 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.
由于宫颈癌死亡率高,治疗选择有限,因此迫切需要开发有效的药物。在此,我们报告了一系列新型有效的 HSP90 靶向 PROTAC 的设计、合成和评估。这些化合物对宫颈癌细胞表现出很强的抗增殖活性,IC 值很低。化合物 lw13 在仅 0.05μM 的浓度下就能有效降解 HSP90。此外,它可以抑制癌细胞的转移,并诱导显著的细胞周期停滞和细胞凋亡。此外,lw13 在体外和体内均表现出显著的抗肿瘤活性,并与顺铂具有协同作用。此外,lw13 可以通过间接降低 HER2 和 AKT 的水平来防止 HER2/AKT/mTOR 信号通路的激活。这项研究为癌症治疗铺平了道路,并为宫颈癌的联合治疗提供了有价值的见解。
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