A-204197, a new tubulin-binding agent with antimitotic activity in tumor cell lines resistant to known microtubule inhibitors

Drug resistance is a prevalent problem in the treatment of neoplastic disea se, and the effectiveness of many clinically useful drugs is limited by the fact that they are substrates for the efflux pump, beta -glycoprotein, Bec ause there is a need for new compounds that are effective in treating drug- resistant tumors, we tested A-204197 (4-[4-acetyi-4,5-dihydro-5-(3,4,5-trim ethoxyphenyl)-1,3,4-oxadiazol-2-yl]-N,N-dimethylbenzeneaminc), a novel oxad iazoline derivative with antiproliferative properties, on cell lines that w ere either sensitive or resistant to known microtubule inhibitors. Cell lin es that were resistant to paclitaxel, vinblastine, or colchicine were equal ly sensitive to A-204197 (proliferation IC(50)s ranging from 36 to 48 nM) d espite their expression levels of beta -glycoprotein, The effect of A-20419 7 on fell growth was associated with cell cycle arrest in G(2)-M, increased phosphorylation of select G(2)(-)M checkpoint proteins, and apoptosis, In competition-binding assays, A-204197 competed with [H-3]labeled colchicine for binding to tubulin (K-i = 0.75 muM); however, it did not compete with [ H-3]-labeled paclitaxel, A-204197 prevented tubulin polymerization in a dos e-dependent manner (IC50 = 4.5 muM) in vitro and depolymerized microtubules in a time-dependent manner in cultured cells. These findings indicate A-20 4197 is a promising new tubulin-binding compound with antimitotic activity that has potential for treating neoplastic diseases with greater efficacy t han currently used antimitotic agents.