Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3)
- Eur J Med Chem. 2021 Jan 15;210:112990. doi: 10.1016/j.ejmech.2020.112990.
- 1. Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland. Electronic address: [email protected].
- 2. Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland.
- 3. Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland.
- 4. Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland; Celon Pharma S.A., Clinical Trials Department, Ogrodowa 2A, Kiełpin, 05-092, Łomianki, Poland.
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 IC50s 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).