Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor
| Autor: | Peter King, Suso Platero, Matthew V. Lorenzi, Kelly Van De Ven, Caroline Paulussen, Liang Xie, Jennifer Yang, Jorge Vialard, Christopher Moy, Eleonora Jovcheva, Timothy Perera, David R. Newell, Jayaprakash Karkera, Sylvie Laquerre, Martin Page, Ron Gilissen, David C. Rees, Neil T. Thompson, George Ward, Desiree De Lange, Laurence Anne Mevellec, Patrick Angibaud, Matthew S Squires, Tinne Verhulst, Na Cheng, Eddy Jean Edgard Freyne, Christopher William Murray, Gordon Saxty |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cancer Research Angiogenesis Antineoplastic Agents Biology Fibroblast growth factor Metastasis Mice 03 medical and health sciences 0302 clinical medicine Erdafitinib Cell Line Tumor Quinoxalines Drug Discovery medicine Animals Humans Molecular Targeted Therapy Phosphorylation Receptor Protein Kinase Inhibitors Cell Proliferation Dose-Response Relationship Drug Kinase medicine.disease Receptors Fibroblast Growth Factor Xenograft Model Antitumor Assays Cell biology Disease Models Animal 030104 developmental biology Oncology Fibroblast growth factor receptor 030220 oncology & carcinogenesis Pyrazoles Lysosomes Tyrosine kinase Protein Binding Signal Transduction |
| Zdroj: | Molecular Cancer Therapeutics. 16:1010-1020 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-16-0589 |
| Popis: | Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010–20. ©2017 AACR. |
| Databáze: | OpenAIRE |
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