Abstract
Purpose
To evaluate the efficacy and oral activity of two promising indoles, (2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone [compound II] and (2-(1H-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.
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Acknowledgments and Disclosures
This work was partially supported by the NIH/NCI [Grant R01CA148706-01A1]. CML, YL, JC, SA, WL, DDM and JTD are inventors on patents related to these compounds and may receive royalties if commercialized.
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Li, CM., Lu, Y., Chen, J. et al. Orally Bioavailable Tubulin Antagonists for Paclitaxel-Refractory Cancer. Pharm Res 29, 3053–3063 (2012). https://doi.org/10.1007/s11095-012-0814-5
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DOI: https://doi.org/10.1007/s11095-012-0814-5