title: Novel microtubule polymerization inhibitor with potent antiproliferative and antitumor activity.
abstract: Microtubule-stabilizing and microtubule-destabilizing agents are commonly used as anticancer agents. Although highly effective, success with these agents has been limited due to their relative insolubility, cumbersome synthesis/purification, toxic side effects, and development of multidrug resistance. Hence, the identification of improved agents that circumvent one or more of these problems is warranted. We recently described the rational design of a series of triazole-based compounds as antimitotic agents. Members of this N-substituted 1,2,4-triazole family of compounds exhibit potent tubulin polymerization inhibition and broad spectrum cellular cytotoxicity. Here, we extensively characterize the in vitro and in vivo effects of our lead compound from the series 1-methyl-5-(3-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-4-yl)-1H-indole, designated T115. We show that T115 competes with colchicine for its binding pocket in tubulin, produces robust inhibition of tubulin polymerization, and disrupts the microtubule network system inside the cells. In addition, T115 arrests human cancer cells in the G(2)-M phase of cell cycling, a hallmark of microtubule destabilizing drugs. T115 also inhibits cell viability of several cancer cell lines, including multidrug-resistant cell lines, in the low nanomolar range. No cytotoxicity was observed by T115 against normal human skin fibroblasts cell lines, and acute toxicity studies in normal nontumor-bearing mice indicated that T115 is well-tolerated in vivo (maximum total tolerated dose, 400 mg/kg). In a mouse xenograft model using human colorectal (HT-29) and prostate (PC3) cancer cells, T115 significantly inhibited tumor growth when administered i.p. Taken together, our results suggest that T115 is a potential drug candidate for cancer chemotherapy.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and the Informatics Institute of University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Arora
authors.forename: Xin I
authors.initials: XI
authors.lastname: Wang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Keenan
authors.forename: Christina
authors.initials: C
authors.lastname: Andaya
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Youyi
authors.initials: Y
authors.lastname: Peng
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D003078:Colchicine