title: Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Janes
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Hansen
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Ulf
authors.initials: U
authors.lastname: Peters
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Kessler
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Yuching
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Kucharski
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Tess
authors.initials: T
authors.lastname: Ely
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Chen
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Firdaus
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Anjali
authors.initials: A
authors.lastname: Babbar
authors.affiliation: Wellspring Biosciences, La Jolla, California.
authors.forename: Pingda
authors.initials: P
authors.lastname: Ren
authors.affiliation: Wellspring Biosciences, La Jolla, California. yi@kuraoncology.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D018631:ras Proteins