title: Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer.
abstract: OBJECTIVE
  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.
authors: Preclinical Research and Development, GTx Inc., Memphis, Tennessee 38163, USA.
authors: Chien-Ming
authors: CM
authors: Li
authors: Yan
authors: Y
authors: Lu
authors: Jianjun
authors: J
authors: Chen
authors: Terrence A
authors: TA
authors: Costello
authors: Ramesh
authors: R
authors: Narayanan
authors: Mara N
authors: MN
authors: Dalton
authors: Linda M
authors: LM
authors: Snyder
authors: Sunjoo
authors: S
authors: Ahn
authors: Wei
authors: W
authors: Li
authors: Duane D
authors: DD
authors: Miller
authors: James T
authors: JT
authors: Dalton
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D000077143:Docetaxel; D004285:Dogs; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; D000077143:Docetaxel; D017239:Paclitaxel; D003078:Colchicine