5KYK

Covalent GTP-competitive inhibitors of KRAS G12C: Guanosine bisphosphonate Analogs

Summary for 5KYK

• Entry DOI: 10.2210/pdb5kyk/pdb
• Descriptor: GTPase KRas, 5'-O-[(R)-[({2-[(chloroacetyl)amino]ethyl}sulfamoyl)methyl](hydroxy)phosphoryl]guanosine (3 entities in total)
• Functional Keywords: kras, cancer, covalent inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 3
• Total formula weight: 59416.80

Authors

Xiong, Y.,Lu, J.,Hunter, J.,Li, L.,Scott, D.,Manandhar, A.,Gondi, S.,Westover, K.D.,Gray, N.S. (deposition date: 2016-07-21, release date: 2017-04-12, Last modification date: 2024-12-25)

Primary citation

Xiong, Y.,Lu, J.,Hunter, J.,Li, L.,Scott, D.,Choi, H.G.,Lim, S.M.,Manandhar, A.,Gondi, S.,Sim, T.,Westover, K.D.,Gray, N.S.
Covalent Guanosine Mimetic Inhibitors of G12C KRAS.
ACS Med Chem Lett, 8:61-66, 2017

PubMed 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 , 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.

PubMed: 28105276
DOI: 10.1021/acsmedchemlett.6b00373

Experimental method

X-RAY DIFFRACTION (2.702 Å)