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G. Saxty



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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-019 - JNJ-42756493 is a potent and selective FGFR1-4 kinase inhibitor with promise for clinical use in patients with FGFR driven tumors (ID 2867)

      09:30 - 16:30  |  Author(s): G. Saxty

      • Abstract

      Background
      The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Focal amplification of FGF receptor 1 (FGFR1) has been identified in a subset of squamous and small cell lung cancers and is associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in these cohorts of patients. A number of small-molecule FGFR targeted agents, with diverse kinase inhibitory and pharmacological profiles, are currently in clinical development.

      Methods
      Fragment-based drug discovery coupled to structure-based design was used to identify JNJ-42756493. Fragments were optimized into potent FGFR inhibitors with selectivity against VEGFR2, which shares 57% sequence identity with the kinase domains of FGFR1 and FGFR3, and 54% with that of FGFR4.

      Results
      JNJ-42756493 has a pharmacological profile that is differentiated from other agents in this class currently under investigation. JNJ-42756493 displays potent pan FGFR (1, 2, 3 and 4) tyrosine kinase inhibitory activity and is highly selective outside the FGFR family. JNJ-42756493 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines dependent upon deregulated FGFR expression. JNJ-42756493 demonstrated highly specific tumor inhibitory effects in FGFR1-4 dependent cell lines in vitro and xenografts in vivo, with no discernible activity in models that were not dependent on FGFR signaling. JNJ-42756493 showed favorable drug like properties and displayed a high distribution to lung tissue. JNJ-42756493 was well tolerated at efficacious doses and resulted in potent dose-dependent antitumor activity accompanied by pharmacodynamic modulation of tumor FGFR and downstream pathway components.

      Conclusion
      Data presented here highlights JNJ-42756493 as a novel, highly potent and selective small-molecule pan FGFR kinase inhibitor with potent antitumor activity against FGFR-deregulated tumors in preclinical models. These data, together with our ongoing Phase 1 clinical trial, position JNJ-42756493 as a differentiated selective pan-FGFR family inhibitor and support its continued clinical development in lung cancer and other malignancies associated with aberrant FGFR signaling.