YM-201627: an orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation.

We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039–0.12μM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01μM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.