Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site
Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site
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DOI：
10.1016/j.chembiol.2018.07.009
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发表时间：
2018-11-15
影响因子：
8.6
通讯作者：
Ikura, Mitsuhiko
中科院分区：
文献类型：
--
作者：
Fang, Zhenhao;Marshal, Christopher B.;Ikura, Mitsuhiko
KRAS在几种最致命的癌症中经常发生突变；然而，KRAS蛋白已被证明是一个具有挑战性的药物靶点。K-RAS4B必须通过预烯基化定位到质膜上才能激活致癌信号，因此我们努力将小分子化合物的蛋白-膜界面作为靶点。虽然所有已报道的先导化合物对溶液中的KRAS的亲和力都很低，但当戊烯基化的K-RAS4B与脂双层结合时，Cmpd2的效力大大增强。我们已经阐明了Cmpd2的一个独特的作用机制，它同时与KRAS上的一个浅口袋结合，并与脂质双层结合，从而使KRAS稳定在膜封闭其效应器结合部位的方向，减少RAF的结合，并削弱RAF的激活。此外，Cmpd2在双层上的浓缩通过促进与KRAS的相互作用来增强效力。这一见解揭示了一种开发膜相关蛋白抑制剂的新方法。
KRAS is frequently mutated in several of the most lethal types of cancer; however, the KRAS protein has proven a challenging drug target. K-RAS4B must be localized to the plasma membrane by prenylation to activate oncogenic signaling, thus we endeavored to target the protein-membrane interface with small-molecule compounds. While all reported lead compounds have low affinity for KRAS in solution, the potency of Cmpd2 was strongly enhanced when prenylated K-RAS4B is associated with a lipid bilayer. We have elucidated a unique mechanism of action of Cmpd2, which simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby stabilizing KRAS in an orientation in which the membrane occludes its effector-binding site, reducing RAF binding and impairing activation of RAF. Furthermore, enrichment of Cmpd2 on the bilayer enhances potency by promoting interaction with KRAS. This insight reveals a novel approach to developing inhibitors of membrane-associated proteins.