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
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-01-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1293728/full |
| _version_ | 1797356927249809408 |
|---|---|
| author | Delfina Popiel Aleksandra Stańczak Monika Skupińska Agata Mikołajczyk Paulina Stańczak Filip Mituła Joanna Hucz-Kalitowska Kinga Jastrzębska Damian Smuga Jakub Dominowski Monika Delis Krzysztof Mulewski Wojciech Pietruś Daria Zdżalik-Bielecka Karolina Dzwonek Monika Lamparska-Przybysz Abdellah Yamani Patrycja Olejkowska Natalia Piórkowska Krzysztof Dubiel Maciej Wieczorek Maciej Wieczorek Jerzy Pieczykolan |
| author_facet | Delfina Popiel Aleksandra Stańczak Monika Skupińska Agata Mikołajczyk Paulina Stańczak Filip Mituła Joanna Hucz-Kalitowska Kinga Jastrzębska Damian Smuga Jakub Dominowski Monika Delis Krzysztof Mulewski Wojciech Pietruś Daria Zdżalik-Bielecka Karolina Dzwonek Monika Lamparska-Przybysz Abdellah Yamani Patrycja Olejkowska Natalia Piórkowska Krzysztof Dubiel Maciej Wieczorek Maciej Wieczorek Jerzy Pieczykolan |
| author_sort | Delfina Popiel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T14:36:53Z |
| format | Article |
| id | doaj.art-07e91621f37e47a8ab05a2c584ceb012 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-08T14:36:53Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-07e91621f37e47a8ab05a2c584ceb0122024-01-12T04:17:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-01-011310.3389/fonc.2023.12937281293728Preclinical 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 cancerDelfina Popiel0Aleksandra Stańczak1Monika Skupińska2Agata Mikołajczyk3Paulina Stańczak4Filip Mituła5Joanna Hucz-Kalitowska6Kinga Jastrzębska7Damian Smuga8Jakub Dominowski9Monika Delis10Krzysztof Mulewski11Wojciech Pietruś12Daria Zdżalik-Bielecka13Karolina Dzwonek14Monika Lamparska-Przybysz15Abdellah Yamani16Patrycja Olejkowska17Natalia Piórkowska18Krzysztof Dubiel19Maciej Wieczorek20Maciej Wieczorek21Jerzy Pieczykolan22Preclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandClinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandMedicinal Chemistry Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandClinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandPreclinical Development Department, Celon Pharma S.A., Kazuń Nowy, PolandFibroblast 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1293728/fullFGFRFGFR inhibitorFGFR aberrationssolid tumortargeted therapyCPL304110 |
| spellingShingle | Delfina Popiel Aleksandra Stańczak Monika Skupińska Agata Mikołajczyk Paulina Stańczak Filip Mituła Joanna Hucz-Kalitowska Kinga Jastrzębska Damian Smuga Jakub Dominowski Monika Delis Krzysztof Mulewski Wojciech Pietruś Daria Zdżalik-Bielecka Karolina Dzwonek Monika Lamparska-Przybysz Abdellah Yamani Patrycja Olejkowska Natalia Piórkowska Krzysztof Dubiel Maciej Wieczorek Maciej Wieczorek Jerzy Pieczykolan 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 Frontiers in Oncology FGFR FGFR inhibitor FGFR aberrations solid tumor targeted therapy CPL304110 |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | FGFR FGFR inhibitor FGFR aberrations solid tumor targeted therapy CPL304110 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1293728/full |
| work_keys_str_mv | AT delfinapopiel preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT aleksandrastanczak preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT monikaskupinska preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT agatamikołajczyk preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT paulinastanczak preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT filipmituła preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT joannahuczkalitowska preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT kingajastrzebska preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT damiansmuga preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT jakubdominowski preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT monikadelis preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT krzysztofmulewski preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT wojciechpietrus preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT dariazdzalikbielecka preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT karolinadzwonek preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT monikalamparskaprzybysz preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT abdellahyamani preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT patrycjaolejkowska preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT nataliapiorkowska preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT krzysztofdubiel preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT maciejwieczorek preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT maciejwieczorek preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer AT jerzypieczykolan preclinicalcharacterizationofcpl304110asapotentandselectiveinhibitoroffibroblastgrowthfactorreceptors12and3forgastricbladderandsquamouscelllungcancer |