Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3)

The FGFR family is characterized by four receptors (FGFR 1-4), binding to 18 ligands called fibroblast growth factors (FGFs). Aberrant activation of FGFs and their FGFRs has been implicated in a broad spectrum of human tumors. We employed the scaffolds hybridization approach, scaffold-hopping concept to synthesize a series of novel pyrazole-benzimidazole derivatives 56 (a-x). Compound 56q (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, -2, -3 with IC(50)s of 0.75 nM, 0.50 nM, 3.05 nM respectively, whereas IC50 of 87.90 nM for FGFR4. Due to its favorable pharmacokinetic profile, low toxicity and potent anti-tumor activity in vivo, compound 56q is currently under evaluation in phase I clinical trial for the treatment of bladder, gastric and squamous cell lung cancers (01FGFR2018; NCT04149691). (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

The FGFR family comprises four receptors (FGFR 1-4) that bind to 18 ligands known as fibroblast growth factors (FGFs). A novel pyrazole-benzimidazole derivative compound 56q has been synthesized and identified as a potent pan-FGFR inhibitor showing low IC50 values for FGFR1, -2, -3. Due to its favorable pharmacokinetic profile, low toxicity, and potent anti-tumor activity, compound 56q is currently undergoing phase I clinical trials for the treatment of bladder, gastric, and squamous cell lung cancers.