Discovery of Orally Bioavailable FGFR2/FGFR3 Dual Inhibitors via Structure-Guided Scafold Repurposing Approach

摘要

Fibroblast growth factor receptors (FGFRs) are transmembrane receptor tyrosine kinases that regulate multiple physiological processes. Aberrant activation of FGFR2 and FGFR3 has been linked to the pathogenesis of many tumor types, including cholangiocarcinoma and bladder cancer. Current therapies targeting the FGFR2/3 pathway exploiting small-molecule kinase inhibitors are associated with adverse events due to undesirable inhibition of FGFR1 and FGFR4. Isoform-specifc FGFR2 and FGFR3 inhibitors that spare FGFR1 and FGFR4 could ofer a favorable toxicity profle and improved therapeutic window to current treatments. Herein we disclose the discovery of dual FGFR2/FGFR3 inhibitors exploiting scafold repurposing of a previously reported ALK2 tool compound. Structure-based drug design and structure-activity relationship studies were employed to identify selective and orally bioavailable inhibitors with equipotent activity toward wild-type kinases and a clinically observed gatekeeper mutant.