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Discovery & pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor

Lookup NU author(s): Professor Herbie Newell

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Abstract

©2017 American Association for Cancer Research. 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.

Publication metadata

Author(s): Perera TPS, Jovcheva E, Mevellec L, Vialard J, De Lange D, Verhulst T, Paulussen C, Van De Ven K, King P, Freyne E, Rees DC, Squires M, Saxty G, Page M, Murray CW, Gilissen R, Ward G, Thompson NT, Newell DR, Cheng N, Xie L, Yang J, Platero SJ, Karkera JD, Moy C, Angibaud P, Laquerre S, Lorenzi MV

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2017

Volume: 16

Issue: 6

Pages: 1010-1020

Print publication date: 01/06/2017

Online publication date: 24/03/2017

Acceptance date: 15/03/2017

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/1535-7163.MCT-16-0589

DOI: 10.1158/1535-7163.MCT-16-0589

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