开发PI3K/mTOR-HSP90连接体结合物,以改善结直肠癌治疗
Zhengyang Wang1, Xiaoyuan Hua1, Chuchu Li1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
European journal of medicinal chemistry
|November 2, 2025
概括
针对细胞外热冲击蛋白90 (eHSP90) 的新型小分子药物联合体 (SMDC) 显示出对结直肠癌 (CRC) 治疗的前景. 这些SMDC增强PI3K/mTOR抑制剂的选择性和有效性,提供了潜在的新治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- PI3K/Akt/mTOR通路的失调对结直肠癌 (CRC) 的发展至关重要.
- 现有的PI3K/mTOR抑制剂在临床应用中面临着有效性有限和选择性差的挑战.
研究的目的:
- 设计新的小分子药物合物 (SMDCs),以提高PI3K/mTOR抑制剂在CRC治疗中的选择性和有效性.
- 为了利用细胞外热冲击蛋白90 (eHSP90) 在瘤中的过度表达,以向药物输送.
主要方法:
- 通过通过可切割的链接器将PI3K/mTOR抑制剂与eHSP90向配体结合,合成SMDCs.
- 在CRC模型中对其结合亲和力,激酶抑制,体外抗增殖活性和体内疗效进行评估的化合物CC-11.
- 通过基因淘汰和机理学研究证实了目标参与和途径抑制.
主要成果:
- CC-11表现出强大的HSP90结合 (15nM) 和PI3Kα抑制 (0.54nM).
- 在实验室中,CC-11对CRC细胞系 (HCT-116,HT-29) 具有优异的抗增殖活性,其选择性比单体对应物高50倍.
- 在体内研究表明,CC-11显著抑制了HCT-116异种移植中的瘤生长 (62.12%),没有可观察到的毒性.
结论:
- 使用HSP90配体的SMDC可以提高PI3K/mTOR抑制剂的选择性和有效性.
- CC-11是针对性CRC治疗的有希望的候选药物,需要进一步优化血稳定性.
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