2. Academic Validation
  3. Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Covalent Guanosine Mimetic Inhibitors of G12C KRAS

  • ACS Med Chem Lett. 2016 Nov 30;8(1):61-66. doi: 10.1021/acsmedchemlett.6b00373.
Yuan Xiong 1,  Jia Lu 2,  John Hunter 2,  Lianbo Li 2,  David Scott 1,  Hwan Geun Choi 3,  Sang Min Lim 4,  Anuj Manandhar 2,  Sudershan Gondi 2,  Taebo Sim 5,  Kenneth D Westover 2,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 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.
  • 2 Departments of Biochemistry and Radiation Oncology, The University of Texas, Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
  • 3 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061, Republic of Korea.
  • 4 Center for Neuro-Medicine, Korea Institute of Science and Technology , Seoul 02792, Republic of Korea.
  • 5 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.
PMID: 28105276 DOI: 10.1021/acsmedchemlett.6b00373
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 compound 11, 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.

Keywords

ActivX; CPM; GDP mimetic; KRAS G12C; bioisostere; bisphosphonate; covalent inhibitor; drug design.

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