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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). Copyright © 2020 Elsevier Masson SAS. All rights reserved.


Abdellah Yamani, Daria Zdżalik-Bielecka, Joanna Lipner, Aleksandra Stańczak, Natalia Piórkowska, Paulina Seweryna Stańczak, Patrycja Olejkowska, Joanna Hucz-Kalitowska, Marta Magdycz, Karolina Dzwonek, Krzysztof Dubiel, Monika Lamparska-Przybysz, Delfina Popiel, Jerzy Pieczykolan, Maciej Wieczorek. Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3). European journal of medicinal chemistry. 2021 Jan 15;210:112990

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PMID: 33199155

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