title: Getting a Handle on RAS-targeted Therapies: Cysteine Directed Inhibitors.
abstract: Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS mutant. In this mini-review, we first assess the development and targeting strategies associated with novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors.
authors.forename: Minh V
authors.initials: MV
authors.lastname: Huynh
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA. campbesl@med.unc.edu.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Campbell
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D003545:Cysteine / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D006153:Guanosine Diphosphate; D018631:ras Proteins; D003545:Cysteine