Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles

Fibroblast Growth Factor Receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform-selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that non-canonical covalent “warheads” based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform )selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low- to subnanomolar potency, efficient covalent inactivation, and excellent selectivity over other FGFRs, kinases with an equivalent cysteine and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability highlighting the potential of SNAr-based approaches in covalent inhibitor design.