Antitumor and Antiangiogenic Activities of BMS-690514, an Inhibitor of Human EGF and VEGF Receptor Kinase Families

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. Clin Cancer Res; 17(12); 4031-41. Ó2011 AACR.

Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer

“…BMS-690514, a reversible oral inhibitor of EGFR, HER-2 and −4, VEGFRs-1 to −3, showed antitumour activity in tumour xenograft models and in cell lines containing the EGFR T790M mutation, suggesting a role against erlotinib-resistant tumours [55]. A phase I/II trial has recently evidenced a modest activity and disease control in both erlotinib-naıve and erlotinib-resistant NSCLC patients [56].…”

Dual HER/VEGF Receptor Targeting Inhibits In Vivo Ovarian Cancer Tumor Growth

“…Cediranib (Recentin, AZD2171) was purchased from Selleckchem (Houston, TX) and Bristol-Myers Squibb (Princeton, NJ) generously provided both AC480 (BMS-599626) and BMS-690514. The chemical structures for cediranib, BMS-599626 and BMS-690514 have previously been reported (20, 32, 36). …”

“…Therefore, we hypothesized that a dual HER/VEGF targeting strategy would effectively limit ovarian cancer tumor growth as compared to either pathway alone. To this end, the pan HER/VEGFR small molecule inhibitor BMS-690514 was employed (32). In a comprehensive kinase inhibition screen, BMS-690514 demonstrated the highest selectivity and potency towards both HER (HER1, HER2 and HER4) and VEGF (VEGFR1, VEGFR2, VEGFR3) family members.…”

Clinical Trials Combining Aromatase Inhibitors with Other Targeted Treatments

“…When BMS-690514 was tested in a panel of breast tumour cell lines, there was a clear demarcation between cell lines that were sensitive and those that were resistant. Overexpression of HER2 seemed to be sufficient to predispose breast tumour cell lines to inhibition by BMS-690514, again underscoring its intrinsic potency to that target [58]. An openlabel randomized, parallel, two-arm phase II study comparing BMS-690514 plus letrozole with lapatinib + letrozole in recurrent/metastatic breast cancer patients who are hormone receptor positive despite HER2 status and who relapsed while receiving or after completing adjuvant anti-endocrine therapy has been completed and results are awaited (NCT01068704) (Table 11.7).…”