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Updated: Mar 10, 2026

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合理设计的强大和口服有效的PI3Kα/δ降解剂的PIK3CA突变乳腺癌没有高血糖责任的强大和有效的PI3Kα/δ降解剂

Yi Hou^1,2,3, Xinqing Zheng^1,2,3, Yiwen Zhang^1,2,3

¹State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and Innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.

Journal of medicinal chemistry

|March 9, 2026

概括

研究人员开发了一种名为D5的新型PROTAC (蛋白质溶解向化马),用于向PI3Kα/δ降解. D5对PIK3CA H1047R突变癌症具有很高的选择性和有效性,可以在没有代谢问题的情况下抑制瘤生长.

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:

使用PROTAC的向蛋白质降解是一种有前途的癌症治疗方法.
选择性PI3K PROTACs的合理设计及其安全概况尚未得到充分确立.
PI3K路径失调,特别是PIK3CA突变,驱动癌症的进展.

研究的目的:

使用结构导向策略开发异型选择性PI3K PROTAC.
与小分子抑制剂相比,评估新型PI3K PROTACs的疗效和安全性.
评估PI3K PROTACs在PIK3CA突变癌症中的治疗潜力.

主要方法:

基于Copanlisib的PROTACs的结构导向设计.
在癌细胞系中评估催化降解效率 (DC50) 和异形选择性.
在>7000个蛋白质中进行非目标分析.
在异种移植模型中对D5化合物的瘤生长抑制和代谢效应的评估.

主要成果:

开发的PROTAC,D5,实现了PI3Kα的高催化降解效率 (DC50 = 0.05nM).
D5对PI3Kα/δ的选择性超过PI3Kβ/γ异型的10,000倍,具有最小的脱效应.
D5在瘤细胞中表现出强烈的敏感性,具有PIK3CA H1047R突变,并在体内显著抑制瘤生长 (65%TGI),没有代谢失调.

结论:

一个结构导向的 PROTAC 开发策略使得创建高度选择性的 PI3Kα/δ 降解剂成为可能.
化合物D5具有强大的抗瘤活性,对PIK3CA H1047R突变癌症具有有利的安全性.
D5代表了对携带PIK3CA H1047R突变的人类乳腺癌的潜在治疗选择.

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