title: Covalent Guanosine Mimetic Inhibitors of G12C KRAS.
abstract: Ras proteins are members of a large family of GTPase enzymes that are commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, of mutant G12C RAS that forms a covalent bond with cysteine 12. Here we report exploration of the structure-activity relationships (SAR) of hydrolytically stable analogues of SML-8-73-1 as covalent G12C KRAS inhibitors. We report the discovery of difluoromethylene bisphosphonate analogues such as compound11, which, despite exhibiting reduced efficiency as covalent G12C KRAS inhibitors, remove the liability of the hydrolytic instability of the diphosphate moiety present in SML-8-73-1 and provide the foundation for development of prodrugs to facilitate cellular uptake. The SAR and crystallographic results reaffirm the exquisite molecular recognition that exists in the diphosphate region of RAS for guanosine nucleotides which must be considered in the design of nucleotide-competitive inhibitors.
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: John
authors.initials: J
authors.lastname: Hunter
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Lianbo
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
authors.forename: David
authors.initials: D
authors.lastname: Scott
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Republic of Korea.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Center for Neuro-Medicine, Korea Institute of Science and Technology , Seoul 02792, Republic of Korea.
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Lim
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Anuj
authors.initials: A
authors.lastname: Manandhar
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Sudershan
authors.initials: S
authors.lastname: Gondi
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
keywords: ActivX; CPM; GDP mimetic; KRAS G12C; bioisostere; bisphosphonate; covalent inhibitor; drug design