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苏兰马德林 (ALRN-6924) 的发现,这是临床开发中的第一个细胞透,稳定α-螺旋的第一个细胞透性

Vincent Guerlavais¹, Tomi K Sawyer¹, Luis Carvajal¹

¹Aileron Therapeutics, Inc., 738 Main Street #398, Waltham, Massachusetts 02451, United States.

Journal of medicinal chemistry

|July 13, 2023

概括

苏兰马德林 (ALRN-6924) 是一种新型的合,可重新激活p53瘤抑制蛋白. 在临床前模型中,它显示出抗癌活性,并保护健康组织免受化疗的影响.

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:

瘤抑制蛋白p53对于预防癌症至关重要.
在野生型TP53癌症中,MDM2和MDMX可以抑制p53,而它们的抑制可以恢复p53功能.
开发针对这些相互作用的药物是癌症治疗的关键策略.

研究的目的:

报告发现和临床前评估的sulanemadlin (ALRN-6924),一个新的p53激活剂.
评估ALRN-6924作为抗癌治疗和化学保护剂的潜力.

主要方法:

开发了一种细胞透,稳定的α-螺旋 (sulanemadlin),模仿p53 N-终端域.
评估ALRN-6924与MDM2和MDMX的结合亲和力.
在TP53-野生型瘤模型中评估ALRN-6924的药理动力学,安全性和抗癌活性.
研究ALRN-6924在健康组织中的化学保护作用.

主要成果:

苏兰马德林 (ALRN-6924) 是第一个进入临床试验的细胞透性合.
ALRN-6924有效地结合并抑制MDM2和MDMX,激活p53信号传递.
该药物在TP53-WT瘤中表现出机理性抗癌活性,并暂时保护健康组织免受化疗.
ALRN-6924表现出有利的药理动力学和安全性概况,活性代谢物通过细胞内蛋白质溶解形成.

结论:

苏兰马德林 (ALRN-6924) 是TP53野生型癌症的一种有前途的新疗法策略.
它作为抗癌剂和化学保护剂的双重作用需要进一步的临床研究.

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