Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor
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- Timothy P.S. Perera
- 1Janssen Research and Development, Beerse, Belgium.
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- Eleonora Jovcheva
- 1Janssen Research and Development, Beerse, Belgium.
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- Laurence Mevellec
- 2Janssen Research and Development, Val de Reuil, France.
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- Jorge Vialard
- 1Janssen Research and Development, Beerse, Belgium.
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- Desiree De Lange
- 1Janssen Research and Development, Beerse, Belgium.
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- Tinne Verhulst
- 1Janssen Research and Development, Beerse, Belgium.
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- Caroline Paulussen
- 1Janssen Research and Development, Beerse, Belgium.
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- Kelly Van De Ven
- 1Janssen Research and Development, Beerse, Belgium.
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- Peter King
- 1Janssen Research and Development, Beerse, Belgium.
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- Eddy Freyne
- 1Janssen Research and Development, Beerse, Belgium.
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- David C. Rees
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- Matthew Squires
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- Gordon Saxty
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- Martin Page
- 1Janssen Research and Development, Beerse, Belgium.
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- Christopher W. Murray
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- Ron Gilissen
- 1Janssen Research and Development, Beerse, Belgium.
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- George Ward
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- Neil T. Thompson
- 3Astex Pharmaceuticals, Cambridge, United Kingdom.
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- David R. Newell
- 4Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
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- Na Cheng
- 5Janssen Research and Development, Shanghai, China.
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- Liang Xie
- 5Janssen Research and Development, Shanghai, China.
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- Jennifer Yang
- 5Janssen Research and Development, Shanghai, China.
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- Suso J. Platero
- 6Janssen Research and Development, Spring House, Pennsylvania.
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- Jayaprakash D. Karkera
- 6Janssen Research and Development, Spring House, Pennsylvania.
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- Christopher Moy
- 6Janssen Research and Development, Spring House, Pennsylvania.
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- Patrick Angibaud
- 2Janssen Research and Development, Val de Reuil, France.
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- Sylvie Laquerre
- 6Janssen Research and Development, Spring House, Pennsylvania.
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- Matthew V. Lorenzi
- 6Janssen Research and Development, Spring House, Pennsylvania.
説明
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
収録刊行物
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- Molecular Cancer Therapeutics
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Molecular Cancer Therapeutics 16 (6), 1010-1020, 2017-06-01
American Association for Cancer Research (AACR)