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

Abstract

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-specific FGFR2 and FGFR3 inhibitors that spare FGFR1 and FGFR4 could offer a favorable toxicity profile and improved therapeutic window to current treatments. Herein we disclose the discovery of dual FGFR2/FGFR3 inhibitors exploiting scaffold 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.

Mining Medicinally Relevant Bioreduction Substrates Inspired by Ligand-Based Drug Design

“…Based on the dataset of known substrates, prediction of enantioselectivity seems unnecessary as long as the reactivity is guaranteed, as stated earlier in Section. Accordingly, a quantitative analysis between the ketone structure and its reactivity was explored, which mirrors the commonly employed structure bioactivity studies in medicinal chemistry projects. − We sought to build SRP models that could predict the reactivity of unknown ketones. As the pharmacophore model perceived the 3D steric features of substrates, we hoped that SRP models could be built upon both steric and electronic features of the molecules.…”