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Asp12的应变释放化使得K-Ras-G12D的突变选择性向成为可能

Qinheng Zheng¹, Ziyang Zhang^2,3, Keelan Z Guiley¹

¹Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.

Nature chemical biology

|March 5, 2024

概括

研究人员开发了新的马洛拉克化合物,以向K-Ras-G12D突变,这是胰腺癌的常见驱动因素. 这些化合物形成稳定的共价键,抑制癌细胞生长和瘤进展.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药用化学医学化学

背景情况:

K-Ras突变是许多人类癌症的关键驱动因素.
目前的疗法针对K-Ras-G12C,但缺乏针对K-Ras-G12D的选择,这种疗法在胰腺癌中很普遍.
准K-Ras-G12D是具有挑战性的,因为没有合适的阿斯巴酸向化学物质.

研究的目的:

开发针对K-Ras-G12D突变的新型共价抑制剂.
通过解决阿斯巴酸盐残留物来克服现有疗法的局限性.
探索基于马洛拉克的电友在K-Ras抑制方面的潜力.

主要方法:

基于马洛拉克的电友的设计和合成.
使用X射线晶体学进行结构洞察.
在GDP和GTP状态下评估K-Ras-G12D的共价交联效率.
在体外和体内评估抑制癌细胞增殖和异种移植瘤生长.

主要成果:

开发出替代性马洛拉克顿,在阿斯巴达-12中选择性地交叉连接K-Ras-G12D.
实现了稳定的共价复合体形成,耐缓冲水解.
在GTP-bound状态下有效抑制下游信号.
显示选择性抑制K-Ras-G12D驱动的癌细胞增殖和异种移植生长.

结论:

基于马洛拉克的电友是针对K-Ras-G12D的一个有希望的策略.
这种方法为由K-Ras-G12D突变驱动的癌症提供了潜在的治疗途径.
开发的化合物在临床前模型中显示出有效性,需要进一步研究.

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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...