Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 210, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112990
Keywords
Anti-tumor activity; FGFR (1-3) inhibitor; Pyrazole-benzimidazole
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Funding
- National Centre for Research and Development Narodowe Centrum Badan i Rozwoju
- Celon Pharma. SA., project CELONKO - Development of modern biomarkers and development of an innovative FGFR kinases inhibitor [STRATEGMED2/266776/17/NCBR/2015]
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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.
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.
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