Discovering innovative drugs depends on the ability to search vast chemical diversity efficiently. Carmot’s discovery technology, Chemotype Evolution, provides rapid access to chemical space relevant to a target of interest. Chemotype Evolution can swiftly and iteratively generate and screen libraries of small molecules or small molecule-peptide hybrids to produce drug leads. The process starts by designing an anchor molecule or “bait”. The bait can be derived from known inhibitors, substrates, co-factors, peptides, hits from a fragment screen, or pharmaceutically acceptable “warheads”. In addition to its target-interacting components, the bait contains a reactive functionality such that it can be linked individually with members of Carmot’s 16,000+ fragment collection, which has been custom-built for the technology over several years focusing on diversity, lead-likeness, low molecular weight, and lipophilicity. The linked molecules (each consisting of a bait and a fragment) constitute a custom library biased towards the target. This customized library is screened to detect binding or modulation of target activity in biochemical or cell-based assays. Chemotype Evolution does not screen pools of compounds; all compounds are synthesized and tested individually. Hits identified from a first iteration screen can be fed into a medicinal chemistry program or converted into new baits and used in a second iteration screen to identify more potent molecules. Alternatively, fragment hits can be repurposed as baits to identify fragments that replace the initial anchor molecule. This process can be repeated as many times as desired. Chemotype Evolution is highly efficient, with tens of thousands of molecules screened per iteration, and does not require protein structural information. This presentation will demonstrate how Chemotype Evolution, medicinal chemistry, and structure-based drug design were combined to discover novel irreversible small molecule inhibitors of the oncogenic G12C mutant form of KRAS that show potent biochemical and cell-based activity.

Use of chemotype evolution to discover novel, potent, irreversible inhibitors of the oncogenic G12C mutant form of KRAS

2019 Spring National Meeting

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