Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer.

Purpose: To evaluate the efficacy and oral activity of two promising indoles, (2-(1 H-indol-3-yl)-1 H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1 H-indol-5-ylamino)-thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound IAT], in paclitaxel- and docetaxel-resistant tumor models in vitro and in vivo. Methods: The in vitro drug-like properties, including potency, solubility, metabolic stability, and drug-drug interactions were examined for our two active compounds. An in vivo pharmacokinetic study and antitumor efficacy study were also completed to compare their efficacy with docetaxel. Results: Both compounds bound to the colchicine-binding site on tubulin, and inhibited tubulin polymerization, resulting in highly potent cytotoxic activity in vitro. While the potency of paclitaxel and docetaxel was compromised in a multidrug-resistant cell line that overexpresses P-glycoprotein, the potency of compounds II and IAT was maintained. Both compounds had favorable drug-like properties, and acceptable oral bioavailability (21-50 %) in mice, rats, and dogs. Tumor growth inhibition of greater than 100 % was achieved when immunodeficient mice with rapidly growing paclitaxel-resistant prostate cancer cells were treated orally at doses of 3-30 mg/kg of II or IAT. Conclusions: These studies highlight the potent and broad anticancer activity of two orally bioavailable compounds, offering significant pharmacologic advantage over existing drugs of this class for multidrug resistant or taxane-refractory cancers. [ABSTRACT FROM AUTHOR]