Synthesis and optimization of LHQ766: A highly selective FGFR2 inhibitor with improved pharmacokinetics

Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by ¹H NMR, ¹³C NMR, HRMS and HPLC analyses. Compound LHQ766 exhibited strong enzymatic inhibition (IC₅₀ = 7.3 nM against FGFR2), good kinase selectivity (selective over FGFR1/3/4 and 72 other tyrosine kinases), and remarkable cellular potency (IC₅₀ = 0.5 nM in BaF3-FGFR2 cells). Mechanistic studies through computational modeling and mass spectrometry revealed LHQ766's covalent binding mode with FGFR2. The compound demonstrated dose-dependent suppression of FGFR2 signaling pathways and selective anti-proliferative effects in FGFR2-driven cancer models. As a key advancement over lead compound 7, LHQ766 showed substantially optimized pharmacokinetic properties, achieving 35.9 % oral bioavailability in rats. These findings positioned LHQ766 as a promising lead compound for targeted FGFR2 therapy.