Abstract
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. 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. 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. By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.
Highlights
The HER family of receptor tyrosine kinases have been of great interest in cancer drug discovery because of their involvement in the biology of diverse cancer types
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
We describe the characterization of the biological activities of BMS-690514 and of its potential as a novel anticancer agent that inhibits both HER receptor signaling in tumor cells and VEGF receptor (VEGFR) signaling in the tumor vasculature
Summary
The HER family of receptor tyrosine kinases have been of great interest in cancer drug discovery because of their involvement in the biology of diverse cancer types. The epidermal growth factor (EGF) receptor is expressed in many epithelial cells and has been shown to be mutated in a subset of non–small cell lung cancer [1]. Erlotinib and gefitinib are small molecule inhibitors of the EGF receptor (EGFR) kinase that have shown efficacy in non–small cell lung cancer patients with EGFR mutations [2]. Authors' Affiliations: 1Oncology Discovery, 2Discovery Chemistry, and 3Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research, Princeton, New Jersey. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Krishnan: Pre-clinical Imaging Consultants, Lawrenceville, NJ 08648
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