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基于MR2的药物发现管道在瘤蛋白KRAS上呈现

Matthias Bütikofer^1,2, Felix Torres^2,3, Harindranath Kadavath^2,4

¹Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 2F 353, Vienna, A-1090, Austria.

Journal of the American Chemical Society

|April 14, 2025

概括

基于碎片的药物发现使用NMR查确定了新型KRAS G12V抑制剂. 一种具有成本效益的NMR方法确定了12个复杂结构,指导癌症治疗药物的优化.

科学领域:

生物化学
结构生物学
医学化学

背景情况:

基于碎片的药物发现 (FBDD) 对于针对KRAS等难以实现的蛋白质至关重要.
在癌症治疗中,KRAS G12V突变是关键的致癌点.

研究的目的:

使用NMR对KRAS G12V进行选.
在FBDD中开发和验证成本效益高的NMR方法.
为结构-活性关系 (SAR) 研究阐明KRAS片段结合模式.

主要方法:

对KRAS G12V-GMP-PNP进行890个片段的NMR查.
用HSQC进行定位实验以识别和确定相关性.
使用基于放松的新波器进行NMR分子替代 (NMR2) 结构计算,不需要同位素标记.

主要成果:

在KRAS SI/SII切换区域内确定了低毫米亲和度的结合剂.
通过成本高效的非同位素标记方法成功确定了12个NMR2KRAS碎片复杂结构.
与传统方法相比验证了NMR2结构的准确性.

结论:

开发的NMR2方法简化了FBDD,允许在没有同位素标记的情况下快速阐明结构.
这种方法为优化KRAS G12V抑制剂提供了关键的SAR见解.
这项研究展示了针对KRAS等具有挑战性的蛋白质的强大,具有成本效益的管道.

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相关概念视频

The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...