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对于选择性抑制KRAS^G12D/RAF1相互作用的序列定义聚胺

Bini Claringbold¹, Steven Vance², Alexandra R Paul¹

¹School of Chemistry and Forensic Science, University of Kent Canterbury Kent CT2 7NH UK.

Chemical science

|November 27, 2024

概括

科学家们开发了新型的合成分子,称为聚胺体,以准KRAS G12D,一种常见的癌症驱动突变. 这些分子有效地抑制了KRAS-RAF相互作用,为难以治疗的癌症提供了新的治疗策略.

科学领域:

药用化学医学化学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

在各种癌症中,RAS蛋白经常发生突变,由于它们在蛋白质-蛋白质相互作用 (PPI) 中的作用,这就带来了重大的治疗挑战.
针对RAS蛋白与下游效应物的相互作用表面,一直是药物发现的一个主要障碍.

研究的目的:

开发一种新的化学平台,即聚胺,用于向蛋白质-蛋白质相互作用 (PPI).
确定KRAS G12D-RAF相互作用的抑制剂,这是癌症扩散的关键途径.

主要方法:

胺酸化学的适应,用于合成近100万个非核酸寡酸序列 (胺酸) 的库.
使用光激活珠子分类 (FABS) 选阻碍KRAS G12D-RAF相互作用的光体.
采用双重质谱和直角验证,用于命中识别和IC50测定.

主要成果:

确定了KRAS G12D的强效基体抑制剂,其IC50值低至25nM.
对于突变KRAS G12D的已识别的抑制剂,其对野生型RAS的选择性非常出色.
在抑制KRAS G12D-RAF相互作用方面验证了聚胺的疗效.

结论:

聚胺体代表了一个有前途的新化学平台,用于针对具有挑战性的蛋白质-蛋白质相互作用 (PPI).
这种方法为开发针对突变RAS驱动癌症的药物提供了潜在的新途径.
该平台对针对其他疾病的PPI具有更广泛的意义,包括神经退行性疾病和病毒感染.

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