Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.

摘要: KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with mutations. Here, we describe ARS-853, a selective, covalent inhibitor KRASG12C that inhibits mutant KRAS–driven signaling by binding to the GDP-bound oncoprotein preventing activation. Based on rates engagement inhibition observed along mutant-specific mass spectrometry–based assay assessing activation status, show nucleotide state is dynamic flux can be modulated upstream factors. These studies provide convincing evidence G12C mutation generates “hyperexcitable” rather “statically active” targeting inactive, form promising approach generating novel anti-RAS therapeutics. Significance: A cell-active, mutant-specific, described targets GDP-bound, inactive prevents subsequent Using this compound, demonstrate rapidly cycles bound responds inputs maintain highly active state. Cancer Discov; 6(3); 316–29. ©2016 AACR . See related commentary Westover et al., [p. 233][1] . This article highlighted In This Issue feature, 217][2] [1]: /lookup/volpage/6/233?iss=3 [2]: /lookup/volpage/6/217?iss=3