Inhibition of Nonfunctional Ras. Issue 2 (18th February 2021)

• Record Type: Journal Article
• Authors: Nussinov, Ruth; Jang, Hyunbum; Gursoy, Attila; Keskin, Ozlem; Gaponenko, Vadim
• Is Part Of: Cell chemical biology. Volume 28:Issue 2(2021)
• Page Start: 121
• Page End: 133
• Publication Date: 2021-02-18
• Subjects: drug discovery -- inhibitor -- kinases -- K-Ras4B -- dimer -- KRAS -- energy landscape; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.12.012
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Intuitively, functional states should be targeted; not nonfunctional ones. So why could drugging the inactive K-Ras4B G12C work—but drugging the inactive kinase will likely not ? The reason is the distinct oncogenic mechanisms. Kinase driver mutations work by stabilizing the active state and/or destabilizing the inactive state. Either way, oncogenic kinases are mostly in the active state. Ras driver mutations work by quelling its deactivation mechanisms, GTP hydrolysis, and nucleotide exchange. Covalent inhibitors that bind to the inactive GDP-bound K-Ras4B G12C conformation can thus work. By contrast, in kinases, allosteric inhibitors work by altering the active-site conformation to favor orthosteric drugs. From the translational standpoint this distinction is vital: it expedites effective pharmaceutical development and extends the drug classification based on the mechanism of action. Collectively, here we postulate that drug action relates to blocking the mechanism of activation, not to whether the protein is in the active or inactive state. Graphical abstract: Abstract : Nussinov et al. describe that the mechanism of mutational activation of kinases differs from Ras. Drug action should relate to the mechanism of activation, not to whether the protein is in active or inactive state. However, allosterically blocking the functional site will work for the inactive kinase and active Ras.