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Ref Type Journal Article
PMID (33199155)
Authors Yamani A, Zdżalik-Bielecka D, Lipner J, Stańczak A, Piórkowska N, Stańczak PS, Olejkowska P, Hucz-Kalitowska J, Magdycz M, Dzwonek K, Dubiel K, Lamparska-Przybysz M, Popiel D, Pieczykolan J, Wieczorek M
Title Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3).
Journal European journal of medicinal chemistry
Vol 210
Issue
Date 2021 Jan 15
URL
Abstract Text 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).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
CPL304110 CPL-304110 FGFR1 Inhibitor 24 FGFR2 Inhibitor 18 FGFR3 Inhibitor 13 CPL304110 inhibits FGFR1, 2, and 3, which may inhibit FGFR signaling pathways, proliferation, and tumor growth (PMID: 33199155).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 amp stomach carcinoma sensitive CPL304110 Preclinical - Cell line xenograft Actionable In a preclinical study, CPL304110 treatment inhibited downstream signaling and proliferation of a gastric carcinoma cell line harboring FGFR2 amplification in culture and inhibited tumor growth in cell line xenograft models (PMID: 33199155). 33199155
FGFR3 S249C bladder carcinoma sensitive CPL304110 Preclinical - Cell culture Actionable In a preclinical study, CPL304110 treatment inhibited proliferation of a bladder carcinoma cell line harboring FGFR3 S249C in culture (PMID: 33199155). 33199155
FGFR1 amp lung non-small cell carcinoma sensitive CPL304110 Preclinical - Cell culture Actionable In a preclinical study, CPL304110 treatment inhibited proliferation of a non-small cell lung cancer cell line harboring FGFR1 amplification in culture (PMID: 33199155). 33199155
FGFR3 fusion FGFR3 amp bladder carcinoma sensitive CPL304110 Preclinical - Cell culture Actionable In a preclinical study, CPL304110 treatment inhibited proliferation of a bladder carcinoma cell line harboring FGFR3 amplification and an FGFR3 fusion in culture (PMID: 33199155). 33199155