Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer

Chien Ming Li, Yan Lu, Jianjun Chen, Terrence A. Costello, Ramesh Narayanan, Mara N. Dalton, Linda M. Snyder, Sunjoo Ahn, Wei Li, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3053-3063
Number of pages11
JournalPharmaceutical Research
Volume29
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

docetaxel
Tubulin
Paclitaxel
Refractory materials
Pharmaceutical Preparations
Drug Stability
Indoles
Tumors
Neoplasms
Cells
Colchicine
P-Glycoprotein
Drug interactions
Drug Interactions
Polymerization
Solubility
Biological Availability
Pharmacokinetics
Prostatic Neoplasms
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

Li, C. M., Lu, Y., Chen, J., Costello, T. A., Narayanan, R., Dalton, M. N., ... Dalton, J. T. (2012). Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer. Pharmaceutical Research, 29(11), 3053-3063. https://doi.org/10.1007/s11095-012-0814-5

Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer. / Li, Chien Ming; Lu, Yan; Chen, Jianjun; Costello, Terrence A.; Narayanan, Ramesh; Dalton, Mara N.; Snyder, Linda M.; Ahn, Sunjoo; Li, Wei; Miller, Duane; Dalton, James T.

In: Pharmaceutical Research, Vol. 29, No. 11, 01.11.2012, p. 3053-3063.

Research output: Contribution to journalArticle

Li, CM, Lu, Y, Chen, J, Costello, TA, Narayanan, R, Dalton, MN, Snyder, LM, Ahn, S, Li, W, Miller, D & Dalton, JT 2012, 'Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer', Pharmaceutical Research, vol. 29, no. 11, pp. 3053-3063. https://doi.org/10.1007/s11095-012-0814-5
Li, Chien Ming ; Lu, Yan ; Chen, Jianjun ; Costello, Terrence A. ; Narayanan, Ramesh ; Dalton, Mara N. ; Snyder, Linda M. ; Ahn, Sunjoo ; Li, Wei ; Miller, Duane ; Dalton, James T. / Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer. In: Pharmaceutical Research. 2012 ; Vol. 29, No. 11. pp. 3053-3063.
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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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AU - Narayanan, Ramesh

AU - Dalton, Mara N.

AU - Snyder, Linda M.

AU - Ahn, Sunjoo

AU - Li, Wei

AU - Miller, Duane

AU - Dalton, James T.

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N2 - 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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