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

Autor: Yamani A; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland. Electronic address: abdellah.yamani@celonpharma.com., Zdżalik-Bielecka D; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Lipner J; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Stańczak A; 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., Piórkowska N; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Stańczak PS; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Olejkowska P; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Hucz-Kalitowska J; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Magdycz M; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Dzwonek K; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Dubiel K; Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Lamparska-Przybysz M; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Popiel D; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Pieczykolan J; Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland., Wieczorek M; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Jan 15; Vol. 210, pp. 112990. Date of Electronic Publication: 2020 Nov 07.
DOI: 10.1016/j.ejmech.2020.112990
Abstrakt: 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 IC 50 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).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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