Arshia Desarkar, & Dr. Edward Njoo
Oncogenic mutations in the GTPase protein KRAS are implicated in approximately 25% of human cancers. Specifically, the G12C mutation, a common mutation found in KRAS-related pathology, is found in 12% of non-small cell lung cancers and 3% of colorectal and other solid tumors. This single residue substitution causes irreversible binding of GTP/GDP to the catalytic site, thereby forcing the protein into a permanent, activated state. While KRAS has been previously considered an undruggable chemotherapeutic target, the discovery of acrylate-based covalent inhibitors of G12C KRAS has led to the development of two FDA-approved drugs: Sotorasib (AMG-510) and Adagrasib (MRTX849) which inspired our own pharmacophore model, and our library of isoxazole-based covalent inhibitors of G12C KRAS. En route, we optimized a previously reported amide coupling in which our library of analogs exhibited a comparatively higher yield of 98%. This transformation tolerates air with a trivial loss of yield and has been applied to 12 different examples of arylmethyl isoxazole acids and alkyl substituted piperazines including in the synthesis of Nucleozin. In vitro potency was then evaluated through MTT assays against Calu-1 cancer cell lines, and to test the selectivity, against HCT-116 cancer cell lines. Our S-methyl compounds were shown to be selective in targeting mutant G12C, as they were ineffective in HCT-116 colon cells, and our lead compound in specificity amongst these contains a 2,6-dichloroaryl ring.