D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity

N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indo-3-yl]-glyoxyl-amid (D-24851) is a novel synthetic compound that was identified in a cell-based screening assa y to discover cytotoxic drugs. D-24851 destabilizes microtubules and blocks cell cycle transition specifically at G(2)-M phase. The binding site of D- 24851 does not overlap with the tubulin binding sites of known microtubule- destabilizing agents like vincristine or colchicine. In vitro, D-24851 has potent cytotoxic activity toward a panel of established human tumor cell li nes including SKOV3 ovarian cancer, U87 glioblastoma, and ASPC-1 pancreatic cancer cells. In vivo, oral D-24851 treatment induced complete tumor regre ssions (cures) in rats bearing Yoshida AH13 sarcomas. Of importance is that the administration of curative doses of D-24851 to the animals revealed no systemic toxicity in terms of body weight loss and neurotoxicity in contra st to the administration of paclitaxel or vincristine. Interestingly, multi drug-resistant cell lines generated by vincristine-driven selection or tran sfection with the M-r 170,000 P-glycoprotein encoding cDNA were rendered re sistant toward paclitaxel, vincristine, or doxorubicin but not towards D-24 851 when compared with the parental cells. Because of its synthetic nature, its oral applicability, its potent in vitro and in vivo antitumoral activi ty, its efficacy against multidrug-resistant tumors, and the lack of neurot oxicity, D-24851 may have significant potential for the treatment of variou s malignancies.