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在PDEδ中用甲基-阿里尔电友对胺酸进行向,会损害K-Ras信号传输

Ruirui Zhang¹, Maxim A Huetzen^2,3,4,5, Aylin Binici^1,6

¹Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Street 11, Dortmund 44227, Germany.

Journal of medicinal chemistry

|January 7, 2026

概括

研究人员开发了一种新型的共价抑制剂Deltafluorine,向蛋白质中的谷氨酸残留物. 这种抑制剂通过在小鼠模型中减少瘤体积,在癌症治疗中显示出有前途.

科学领域:

化学生物学化学生物学
药用化学医学化学
在瘤学瘤学.

背景情况:

针对低反应性碳酸盐的有针对性的共价修饰具有挑战性.
蛋白质工程使得阿斯巴酸盐残留物的共价修饰成为可能.
开发用于选择性共价向的新策略对于药物发现至关重要.

研究的目的:

在蛋白质结合部位中对酸性残留物进行共价向的稳定配体的工程.
开发一种用于向谷氨酸残留物的新型共价抑制剂.
在癌症的细胞和动物模型中评估抑制剂的疗效.

主要方法:

利用陪伴者PDEδ来运送脂化上蛋白.
配备有基于化的基电的非共价抑制剂.
合成并测试了Deltafluorine,这是一种新型的抑制剂,具有3-甲基-皮里迪尔组.
评估了对核爱素 (谷氨,酸盐,酸盐,酸盐) 的抑制剂稳定性.
评估细胞活动和抑制MAP-激酶和Akt-mTOR通路.
在KrasG12D驱动的肺腺癌的土著小鼠模型中测试了DeltaFluorine.

主要成果:

在PDEδ连接体结合部位中,证明了特定的谷氨酸残留物 (p.E88) 的共价变异.
德尔塔氨酸对常见的核友菌具有稳定性.
在细胞中,deltafluorine表现出不同的非共价和共价反应特征.
观察到抑制了MAP-激酶和Akt-mTOR信号通路.
在KrasG12D驱动的肺腺癌小鼠模型中实现了显著的瘤体积减少.

结论:

工程结合体可以使酸性残留的共价向成为可能.
德尔塔氨酸是一种强大的共价抑制剂,向谷氨酸残留物.
德尔塔氨酸显示出对侵袭性肺腺癌的治疗潜力.

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Small GTPases - Ras and Rho

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:

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.
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