Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Frontiers in oncology	13		2023	1293728	Front Oncol

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	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
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