Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor.
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.
Janssen Research and Development, Beerse, Belgium.
Timothy P S
TPS
Perera
Janssen Research and Development, Beerse, Belgium.
Eleonora
E
Jovcheva
Janssen Research and Development, Val de Reuil, France.
Laurence
L
Mevellec
Janssen Research and Development, Beerse, Belgium.
Jorge
J
Vialard
Janssen Research and Development, Beerse, Belgium.
Desiree
D
De Lange
Janssen Research and Development, Beerse, Belgium.
Tinne
T
Verhulst
Janssen Research and Development, Beerse, Belgium.
Caroline
C
Paulussen
Janssen Research and Development, Beerse, Belgium.
Kelly
K
Van De Ven
Janssen Research and Development, Beerse, Belgium.
Peter
P
King
Janssen Research and Development, Beerse, Belgium.
Eddy
E
Freyne
Astex Pharmaceuticals, Cambridge, United Kingdom.
David C
DC
Rees
Astex Pharmaceuticals, Cambridge, United Kingdom.
Matthew
M
Squires
Astex Pharmaceuticals, Cambridge, United Kingdom.
Gordon
G
Saxty
Janssen Research and Development, Beerse, Belgium.
Martin
M
Page
Astex Pharmaceuticals, Cambridge, United Kingdom.
Christopher W
CW
Murray
Janssen Research and Development, Beerse, Belgium.
Ron
R
Gilissen
Astex Pharmaceuticals, Cambridge, United Kingdom.
George
G
Ward
Astex Pharmaceuticals, Cambridge, United Kingdom.
Neil T
NT
Thompson
Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
David R
DR
Newell
Janssen Research and Development, Shanghai, China.
Na
N
Cheng
Janssen Research and Development, Shanghai, China.
Liang
L
Xie
Janssen Research and Development, Shanghai, China.
Jennifer
J
Yang
Janssen Research and Development, Spring House, Pennsylvania.
Suso J
SJ
Platero
Janssen Research and Development, Spring House, Pennsylvania.
Jayaprakash D
JD
Karkera
Janssen Research and Development, Spring House, Pennsylvania.
Christopher
C
Moy
Janssen Research and Development, Val de Reuil, France.
Patrick
P
Angibaud
Janssen Research and Development, Spring House, Pennsylvania.
Sylvie
S
Laquerre
Janssen Research and Development, Spring House, Pennsylvania. mlorenzi@its.jnj.com.
Matthew V
MV
Lorenzi
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011810:Quinoxalines; D017468:Receptors, Fibroblast Growth Factor; C000604580:erdafitinib