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

作者：Timothy Pietro Suren Perera, Eleonora Jovcheva, Laurence Mévellec, Jorge E. Vialard, Desiree De Lange, Tinne Verhulst, Caroline Paulussen, Kelly Van De Ven, Peter King, Eddy J. E. Freyne, David C. Rees, Matthew S. Squires, Gordon Saxty, Martin Pagé, Christopher W. Murray, Ron Gilissen, George A. Ward, Neil T. Thompson, David R. Newell, Na Cheng, Liang Xie, Jennifer Yang, Suso J. Platero, Jayaprakash D. Karkera, Christopher H. Moy, Patrick R. Angibaud, Sylvie G. Laquerre, Matthew V. Lorenzi · 发表于：Molecular Cancer Therapeutics · 年份：2017 · DOI：10.1158/1535-7163.mct-16-0589 · 被引用次数：348 · 研究领域：Fibroblast Growth Factor Research、Lung Cancer Treatments and Mutations、Chronic Myeloid Leukemia Treatments

Abstract 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.