Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State
复制标题
DOI：
10.1158/2159-8290.cd-15-1105
复制
发表时间：
2016-03-01
期刊：
影响因子：
28.2
通讯作者：
Liu, Yi
中科院分区：
文献类型：
--
作者：
Patricelli, Matthew P.;Janes, Matthew R.;Liu, Yi
KRAS功能获得性突变发生在大约30%的人类癌症中。尽管有30多年以KRAS为重点的研究和开发工作，但尚未发现针对KRAS突变癌症的靶向治疗。在这里，我们描述了ARS-853，一种选择性的KRAS（G12 C）共价抑制剂，通过与GDP结合的癌蛋白结合并阻止激活来抑制突变KRAS驱动的信号传导。基于ARS-853观察到的接合和抑制率，沿着用于评估KRAS活化状态的基于质谱的多核苷酸特异性测定，我们表明KRAS（G12 C）的核苷酸状态处于可由上游信号传导因子调节的动态通量状态。这些研究提供了令人信服的证据表明，KRAS（G12 C）突变产生一个“超兴奋”，而不是一个“静态活性”的状态，并针对无活性，GDP结合的形式是一个有前途的方法，用于产生新的抗RAS therapeutic.Significance：一个细胞活性，muplatin特异性，共价抑制剂KRAS（G12 C）的描述，靶向GDP结合，无活性状态，并防止随后的激活。使用这种新化合物，我们证明KRAS（G12 C）癌蛋白快速循环结合核苷酸，并响应上游信号输入，以保持高度活性状态。(C)2016年AACR。
KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics.SIGNIFICANCE: A cell-active, mutant-specific, covalent inhibitor of KRAS(G12C) is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS(G12C) oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. (C) 2016 AACR.