Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

• Published in: Molecular cancer therapeutics 2017-06, Vol.16 (6), p.1010-1020
• Main Authors: Perera, Timothy P S, Jovcheva, Eleonora, Mevellec, Laurence, Vialard, Jorge, De Lange, Desiree, Verhulst, Tinne, Paulussen, Caroline, Van De Ven, Kelly, King, Peter, Freyne, Eddy, Rees, David C, Squires, Matthew, Saxty, Gordon, Page, Martin, Murray, Christopher W, Gilissen, Ron, Ward, George, Thompson, Neil T, Newell, David R, Cheng, Na, Xie, Liang, Yang, Jennifer, Platero, Suso J, Karkera, Jayaprakash D, Moy, Christopher, Angibaud, Patrick, Laquerre, Sylvie, Lorenzi, Matthew V
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antitumor activity; Biological activity; Cancer; Cell culture; Cell Line, Tumor; Cell Proliferation - drug effects; Controlled release; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Embryogenesis; Embryonic growth stage; Extracellular signal-regulated kinase; Fibroblast growth factor receptors; Humans; Inhibitors; Kinases; Lysosomes - metabolism; Male; Metastases; Mice; Molecular Targeted Therapy; Pharmacodynamics; Pharmacology; Phosphorylation; Protein Binding; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Pyrazoles - administration & dosage; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Quinoxalines - administration & dosage; Quinoxalines - pharmacokinetics; Quinoxalines - pharmacology; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Signal Transduction - drug effects; Signaling; Sustained release; Tumor cell lines; Tumors; Tyrosine; Wound healing; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-16-0589

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 ( ) 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. .