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发现一种第一类降解脂类激酶PIKfyveveve的降解剂

Chungen Li¹, Yuanyuan Qiao^2,3, Xia Jiang²

¹State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Roadd, Shanghai 200032, People's Republic of China.

Journal of medicinal chemistry

|August 22, 2023

概括

一种新的PIKfyve降解剂,PIK5-12d,通过降解PIKfyve蛋白来有效向前列腺癌. 这种新方法对开发基于PIKfyve的向癌症疗法充满希望.

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:

酸酸酸酶PIKfyve是癌症中潜在的治疗点.
现有的PIKfyve抑制剂在临床上取得了有限的成功.

研究的目的:

通过蛋白质溶解向嵌合体 (PROTAC) 方法发现一流的PIKfyve降解剂.
在前列腺癌模型中评估新型降解剂PIK5-12d的疗效.

主要方法:

使用PROTAC的方法来设计和合成PIKfyve降解剂12d (PIK5-12d).
在前列腺癌VCaP细胞中评估PIKfyve降解强度 (DC50,Dmax).
研究了降解机制,包括VHL和蛋白质组依赖性.
评估了PIK5-12d对VCaP细胞生长,自和下游信号传导的影响.
在腹腔内给药后评估的体内疗效.

主要成果:

在VCaP细胞中,PIK5-12d强烈降解了PIKfyve蛋白 (DC50 = 1.48nM,Dmax = 97.7%).
降解是选择性的,并且依赖于VHL和蛋白质组.
在前列腺癌细胞中,PIK5-12d诱导了细胞质真空化,并阻断了自流.
PIK5-12d比原始抑制剂更有效地抑制癌细胞生长,并显示长时间的信号抑制.
在体内给药导致强大的PIKfyve降解和抑制瘤增殖.

结论:

PIK5-12d是第一类的PIKfyve降解剂,具有强大的抗癌活性.
PIK5-12d显示出比抑制剂更高的疗效,并且在体内显示出有希望的结果.
PIK5-12d作为一种有价值的化学工具,用于推进PIKfyve向癌症治疗.

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