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|Ref Type||Journal Article|
|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|
|Date||2021 Jan 15|
|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).|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CPL304110||CPL-304110||FGFR1 Inhibitor 27 FGFR2 Inhibitor 22 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|