The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a highly informative set of ligand-complexed co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C.  Key molecular interactions with the protein were optimized, with the potency of lead compounds evaluated by (a) mass spectrometric quantification of modified KRAS protein with and without treatment of test compounds, and (b) measurement of phospho-ERK in a whole-cell assay using H358 cells after incubation with test compounds for 3 hours. These efforts identified MRTX1257 as a potent and selective inhibitor of mutant KRAS G12C activity. This lead compound was utilized as a research tool to aid in a deeper understanding of therapeutic susceptibility and KRAS dependence.  MRTX1257 makes a covalent bond with the codon 12 cysteine and binds in the “Switch-2” pocket of KRAS, stabilizing the protein in the inactive, GDP-bound state.  MRTX1257 contains a cyanomethyl group that displaces a water found near Gly10 in co-crystal structures of less potent analogs and contains an 8-methylnaphthyl group that fills a hydrophobic pocket resulting in enhanced potency compared with unsubstituted naphthyl analogs.  MRTX1257 demonstrated rapid, irreversible modification of GDP-bound recombinant KRAS G12C and suppressed ERK phosphorylation with an IC<sub>50 </sub>= 1 nM in the H358 cell line.  In proteomics studies designed to assess global protein modification, MRTX1257 was shown to be highly selective for the targeted Cys12 of KRAS G12C versus other surface-exposed cysteine residues in NCI-H358 cells.  Finally, at a 30mg/kg PO dose, MRTX1257 exhibited 31% bioavailability in mouse, demonstrated near complete inhibition of KRAS signaling in tumor tissue, and complete durable tumor regression in MIA PaCa-2 xenografts. The discovery of the tetrahydropyridopyrimidine series, the structure-based optimization to MRTX1257 and its preclinical potency, selectivity, ADME and efficacy profile will be presented.<br/>

Structure-based drug discovery of MRTX1257: A selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer

2019 Spring National Meeting

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