SUPPRESSION OF MICROTUBULE DYNAMICS BY LY290181 - A POTENTIAL MECHANISM FOR ITS ANTIPROLIFERATIVE ACTION

LY290181, (3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile, is a pote nt antiproliferative compound that blocks cells in the G(2)/M phase of the cell cycle by an apparent action on microtubules. In the present work we found that LY290181 bound to tubulin with high affinity (1 mol of LY290181 per mol of tubulin dimer; K-a, 3.8 x 10(5) M(-1)) and tha t it did not appear to bind at the colchicine or vinblastine-binding s ites, LY290181 strongly stabilized microtubule dynamics as determined by video microscopy. It reduced the rate and extent of growing and sho rtening, reduced the catastrophe frequency and increased the rescue fr equency, and increased the percentage of time the microtubules spent i n an attenuated state, At the lowest effective LY290181 concentrations (0.1-0.3 mu M), suppression of dynamics occurred with little reductio n in polymer mass, However, at higher concentrations, LY290181 strongl y reduced the polymer mass with half-maximal inhibition at a concentra tion of 0.75 mu M. We suggest that LY290181 may exert its antiprolifer ative activity by stabilizing spindle microtubule dynamics by binding to tubulin at a novel site.