1. Academic Validation
  2. Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families

Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families

  • Clin Cancer Res. 2011 Jun 15;17(12):4031-41. doi: 10.1158/1078-0432.CCR-10-3417.
Tai W Wong 1 Francis Y Lee Stuart Emanuel Craig Fairchild Joseph Fargnoli Brian Fink Ashvinikumar Gavai Amy Hammell Benjamin Henley Christine Hilt John T Hunt Bala Krishnan Daniel Kukral Anne Lewin Harold Malone Derek Norris Simone Oppenheimer Gregory Vite Chiang Yu
Affiliations

Affiliation

  • 1 Oncology Discovery, Discovery Chemistry, and Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research, Princeton, NJ 08543, USA. tai.wong@bms.com
Abstract

Purpose: The extensive involvement of the HER kinases in epithelial Cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514.

Experimental design: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI.

Results: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces Apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy.

Conclusions: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.

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