Mutationally activated kinases are a major cause of aberrant cancer cell growth.  Several kinases are currently being pursued as drug targets for cancer chemotherapy, including the ErbB family of enzymes, VEGFR, and FGFR, among others. Despite their clinical success, small molecule kinase inhibitors often lose their effectiveness in tumors over time as a consequence of secondary mutations that significantly decrease the drug-enzyme binding affinity.  To overcome this type of acquired tumor resistance, irreversible inhibitors that covalently attach to the ATP binding pocket have been introduced. Using this strategy, we have designed kinase inhibitors containing cysteine-binding metal-based electrophiles.  The compounds feature organic ATP-mimicking scaffolds that bind to the target kinase active site with high affinity and selectivity while the electrophilic metal induces a permanent coordinative bond with the amino acid residue to achieve irreversible inhibition.  Here, we present the structure-guided design and synthesis of this class of molecules.  Several of the target molecules showed binding constants (Kd) in the low-nanomolar range in competition binding assays and high selectivity for the targeted kinase domain in a panel of 145 wild-type and clinically relevant mutated kinases (KinomeScan, DiscoverX, Fremont, CA).   The ability of the electrophilic agents to induce irreversible adducts was studied by LC ESI-MS/MS in pepsin digests of kinase incubated with inhibitor. Finally, the in-vitro cytotoxicity of selected derivatives was studied in solid tumor cell lines.  The data generated in this study suggest that the new pharmacophores may have applications as therapeutics capable of overcoming acquired tumor resistance by irreversibly inhibiting deregulated kinases.

Targeting cancer-related kinases with metal-functionalized inhibitors

247th National Meeting (2014)

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