KRASG12C is a common driver oncogene of non-small cell lung cancer where it is estimated to exist in ~12% of lung carcinomas. Although small molecules targeting GDP bound, inactive KRASG12C have shown efficacy in KRASG12C preclinical models, we envisioned that directly targeting the active GTP-bound form of KRASG12C would be the preferred route of pharmacological inhibition of KRASG12C with therapeutic advantages. We have identified proprietary ‘beyond rule of five’ small molecule compounds that selectively and covalently inhibit GTP bound KRASG12C. Mechanistically inspired by natural products such as sanglifehrin, our inhibitors first bind to a presenter protein cyclophilin A (CYPA) to form a binary complex. This binary complex then recognizes and binds to GTP bound KRASG12C forming a ternary complex that inhibits downstream signaling. Structure-based drug design efforts led to the discovery of potent and highly selective covalent inhibitors of GTP bound KRASG12C that disrupt the KRASG12C RAF interaction in biochemical assays. The ternary binding interactions were further characterized in kinact/KI analysis. These compounds demonstrate KRASG12C and CYPA dependent cellular pERK inhibition and anti-proliferation effects that correlate well with their biochemical potencies. High selectivity in the cellular setting was confirmed by cysteinome profiling. Importantly, the cellular pharmacology of GTP-KRASG12C inhibitors is differentiated from GDP-KRASG12C targeting compounds (e.g. ARS-1620) as the cellular activity of ARS-1620 is significantly attenuated by growth factor treatment to mimic the tumor microenvironment. Under the same conditions, the activity of GTP-KRASG12C inhibitors is not affected. To our knowledge, these are the first examples of mutant-selective KRAS inhibitors that target the GTP bound KRASG12C. We are currently optimizing the drug-like properties of these covalent inhibitors and evaluating their activity in in vivo models.

Discovery of small-molecule inhibitors of GTP bound KRASG12C

2019 Spring National Meeting

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