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2-Aroylindoles, a Novel Class of Potent, Orally Active Small Molecule Tubulin Inhibitors¹

ASTA Medica Oncology, D-60314 Frankfurt/Main [T. B., T. R., M. S.]; Tumor Biology Center, D-79106 Freiburg [H. H. F., A. M. B.]; Department of Internal Medicine/German Cancer Center, University of Essen Medical School, 45112 Essen [U. V.]; and Faculty of Chemistry and Pharmacy, Institute of Pharmacy, University Regensburg, D-93040 Regensburg [S. M., H. P., J. H., M. F., H. H.] Germany

2-Aroylindoles with 5-methoxy-1H-2-indolyl-phenylmethanone (D-64131) as the lead structure were discovered as a new class of synthetic, small molecule tubulin inhibitors. By competitively binding with [³H]colchicine to ß-tubulin and inhibiting microtubule formation, cycling cells were arrested in the G₂-M phase of the cell division cycle. The proliferation of tumor cells from 12 of 14 different organs and tissues was inhibited with mean IC₅₀s of 62 nM and 24 nM by D-64131 and D-68144, respectively, comparable with the potency of paclitaxel with mean IC₅₀ of 10 nM. By measuring the cytotoxicity in a human colon carcinoma cell model with ectopic ecdysone-inducible expression of the cyclin-dependent kinase inhibitor p21^WAF1, specificity toward cycling cells was demonstrated. In contrast to microtubule inhibitors from natural sources, 2-aroylindoles did not alter the polymerization-dependent GTPase activity of ß-tubulin and are not substrates of the multidrug resistance/multidrug resistance protein efflux pump. No cross-resistance toward cell lines with multidrug resistance/multidrug resistance protein independent resistance phenotypes became evident. In animal studies, no signs of systemic toxicity were observed after p.o. dosages of up to 400 mg/kg of D-64131. In xenograft experiments with the human amelanoic melanoma MEXF 989, D-64131 was highly active with treatment resulting in a growth delay of 23.4 days at 400 mg/kg. Therefore, D-64131 and analogues have the potential to be developed for cancer therapy, replacing or supplementing standard therapy regimens with tubulin-targeting drugs from natural sources.

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