The mechanism of action of a novel antiproliferative compound
LY290181 [2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)
pyran-3-carbonitrile] was characterized.
LY290181 is a potent inhibitor of cell proliferation, producing 50% inhibition of vascular smooth muscle, endothelial, Chinese hamster ovary, HeLa, and human
erythroleukemia cells at concentrations of 8-40 nM. Cell cycle analysis showed that
LY290181 caused accumulation of smooth muscle cells at the G2/M phase and induced mitotic arrest in Chinese hamster ovary cells and HeLa cells. At low concentrations (3-30 nM),
LY290181 blocked transition of cells from metaphase to anaphase and disrupted mitotic spindle organization. At high concentrations (>/=100 nM),
LY290181 produced a concentration-dependent loss of cytoplasmic and spindle microtubules.
LY290181 inhibited the polymerization of purified bovine brain microtubule
protein into microtubules, and it depolymerized preformed microtubules. Using tubulin-1-anilino-8-naphthalene sulfonate complex fluorescence, we have shown that
LY290181 directly interacted with
tubulin in a unique manner. These studies show that
LY290181 induces cell growth arrest in prometaphase/metaphase, and
tubulin appears to be its molecular target.