title: Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor.
abstract: We report the synthesis of a GDP analogue, SML-8-73-1, and a prodrug derivative, SML-10-70-1, which are selective, direct-acting covalent inhibitors of the K-Ras G12C mutant relative to wild-type Ras. Biochemical and biophysical measurements suggest that modification of K-Ras with SML-8-73-1 renders the protein in an inactive state. These first-in-class covalent K-Ras inhibitors demonstrate that irreversible targeting of the K-Ras guanine-nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (USA); Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115 (USA); Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 (USA).
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lim
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.forename: Rane A
authors.initials: RA
authors.lastname: Harrison
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.forename: Martin
authors.initials: M
authors.lastname: Carrasco
authors.forename: John
authors.initials: J
authors.lastname: Hunter
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D020134:Catalytic Domain / Q000235:genetics*; D015195:Drug Design; D015398:Signal Transduction; D018631:ras Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D018631:ras Proteins
keywords: K-Ras; cancer; covalent inhibitors; drug design