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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).
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
CPL304110 CPL304110 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CPL304110 CPL-304110 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 FGFR3 Inhibitor 19 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
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 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
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