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

Timothy P S Perera1, Eleonora Jovcheva1, Laurence Mevellec2

  • 1Janssen Research and Development, Beerse, Belgium.

Molecular Cancer Therapeutics
|March 26, 2017
PubMed

Insights

Erdafitinib (JNJ-42756493) is a potent FGFR inhibitor that demonstrates significant antitumor activity in models with Fibroblast Growth Factor Receptor pathway alterations. This supports its clinical investigation for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Fibroblast growth factor (FGF) signaling is crucial in development and cancer.
  • Alterations in Fibroblast Growth Factor Receptor (FGFR) genes drive tumor growth, metastasis, and angiogenesis.
  • Targeting FGFR is a promising strategy in cancer therapy.

Purpose of the Study:

  • To evaluate the efficacy and mechanism of action of JNJ-42756493 (erdafitinib), a novel FGFR inhibitor.
  • To determine the antitumor activity of erdafitinib in preclinical cancer models with FGFR alterations.

Main Methods:

  • In vitro assessment of JNJ-42756493's tyrosine kinase inhibitory activity against FGFRs.
  • Cellular uptake and FGFR signaling inhibition studies.
  • In vivo efficacy studies using human tumor xenografts with activating FGFR alterations.

Main Results:

  • JNJ-42756493 potently inhibits all four FGFR family members.
  • The drug exhibits prolonged FGFR signaling inhibition due to lysosomal uptake and sustained release.
  • Dose-dependent antitumor activity and modulation of FGFR signaling markers (phospho-FGFR, phospho-ERK) were observed in xenografts.

Conclusions:

  • JNJ-42756493 displays potent and sustained FGFR inhibition with significant antitumor efficacy.
  • Preclinical data strongly support the clinical development of erdafitinib for cancers with FGFR pathway alterations.

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