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Ref Type Journal Article
PMID (38282676)
Authors Popiel D, Stańczak A, Skupińska M, Mikołajczyk A, Stańczak P, Mituła F, Hucz-Kalitowska J, Jastrzębska K, Smuga D, Dominowski J, Delis M, Mulewski K, Pietruś W, Zdżalik-Bielecka D, Dzwonek K, Lamparska-Przybysz M, Yamani A, Olejkowska P, Piórkowska N, Dubiel K, Wieczorek M, Pieczykolan J
Title Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer.
URL
Abstract Text Fibroblast Growth Factor Receptors (FGFRs) are a family of receptor tyrosine kinases expressed on a plethora of cell membranes. They play crucial roles in both embryonic development and adult tissue functions. There is an increasing amount of evidence that FGFR-mediated oncogenesis is mainly related to gene amplification, activating mutations, or translocation in tumors of various histological types. Dysregulation of FGFRs has been implicated in a wide variety of neoplasms, such as bladder, gastric, and lung cancers. Given their functional significance, FGFRs emerge as promising targets for cancer therapy. Here, we introduce CPL304100, an innovative and highly potent FGFR1-3 kinase inhibitor demonstrating excellent in vitro biological activity. Comprehensive analyses encompassed kinase assays, cell line evaluations, PK/PD studies surface plasmon resonance studies, molecular docking, and in vivo testing in mouse xenografts. CPL304110 exhibited a distinctive binding profile to FGFR1/2/3 kinase domains, accompanied by a good safety profile and favorable ADMET parameters. Selective inhibition of tumor cell lines featuring active FGFR signaling was observed, distinguishing it from cell lines lacking FGFR aberrations (FGFR1, 2, and 3). CPL304110 demonstrated efficacy in both FGFR-dependent cell lines and patient-derived tumor xenograft (PDTX) in vivo models. Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

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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
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 lung non-small cell carcinoma sensitive CPL304110 Preclinical - Pdx Actionable In a preclinical study, CPL304110 inhibited tumor growth in a patient-derived xenograft (PDX) model of FGFR2-amplified non-small cell lung cancer, however, regrowth was observed after treatment was stopped (PMID: 38282676). 38282676
FGFR2 amp endometrial cancer sensitive CPL304110 Preclinical - Cell culture Actionable In a preclinical study, CPL304110 inhibited viability of an FGFR2-amplified endometrial cancer cell line in culture (PMID: 38282676). 38282676
FGFR3 S249C urinary bladder cancer sensitive CPL304110 Preclinical - Cell line xenograft Actionable In a preclinical study, CPL304110 inhibited Erk phosphorylation in a bladder cancer cell line harboring FGFR3 S249C in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38282676). 38282676
FGFR2 amp stomach cancer sensitive CPL304110 Preclinical - Pdx & cell culture Actionable In a preclinical study, CPL304110 inhibited Erk phosphorylation and viability in an FGFR2-amplified gastric cancer cell line in culture, inhibited growth in a cell line xenograft model, and induced tumor regression in a patient-derived xenograft (PDX) model (PMID: 38282676). 38282676