Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291

BMS-275291 is an p.o. bioavailable, sulfhydryl-based matrix metalloproteina se (MMP) inhibitor currently in clinical development for the treatment of c ancer. This inhibitor was designed to potently inhibit MMP activities while minimally affecting those of other metalloproteases (e.g., sheddases) invo lved in the release of cell-associated molecules such as tumor necrosis fac tor-alpha, tumor necrosis factor-alpha receptor, interleukin-6 receptor, or L-selectin. In vitro, BMS-275291 is a potent inhibitor (nM) of the activit ies of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14. BMS-275291 inhibits tumor gr owth in a B16BL6 model of experimental metastasis, and in this model, BMS-2 75291 treatment results in a dose-dependent reduction in the number of lung metastases compared with vehicle controls. BMS-275291 also inhibits angiog enesis in a murine angiogenesis model, where once daily treatment with BMS- 275291 results in a dose-dependent inhibition of endothelial cell migration into s.c. implanted Matrigel plugs. Pharmacokinetic studies demonstrated t hat the plasma concentrations of parent BMS-275291 in mice exceeds the in v itro IC50 values for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-14 for at least 4 h after the administration of a therapeutic dose of BMS-275291. Taken toget her, these data demonstrate that BMS-275291 inhibits MMP activities that co ntribute to tumor metastasis and angiogenesis.