title: TTI-237: a novel microtubule-active compound with in vivo antitumor activity.
abstract: 5-Chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine butanedioate (TTI-237) is a microtubule-active compound of novel structure and function. Structurally, it is one of a class of compounds, triazolo[1,5a]pyrimidines, previously not known to bind to tubulin. Functionally, TTI-237 inhibited the binding of [(3)H]vinblastine to tubulin, but it caused a marked increase in turbidity development that more closely resembled the effect observed with docetaxel than that observed with vincristine. The morphologic character of the presumptive polymer is unknown at present. When applied to cultured human tumor cells at concentrations near its IC(50) value for cytotoxicity (34 nmol/L), TTI-237 induced multiple spindle poles and multinuclear cells, as did paclitaxel, but not vincristine or colchicine. Flow cytometry experiments revealed that, at low concentrations (20-40 nmol/L), TTI-237 produced sub-G(1) nuclei and, at concentrations above 50 nmol/L, it caused a strong G(2)-M block. The compound was a weak substrate of multidrug resistance 1 (multidrug resistance transporter or P-glycoprotein). In a cell line expressing a high level of P-glycoprotein, the IC(50) of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold, respectively. TTI-237 was not recognized by the MRP or MXR transporters. TTI-237 was active in vivo in several nude mouse xenograft models of human cancer, including LoVo human colon carcinoma and U87-MG human glioblastoma, when dosed i.v. or p.o. Thus, TTI-237 has a set of properties that distinguish it from other classes of microtubule-active compounds.
authors.affiliation: Discovery Oncology, Wyeth Research, Pearl River, New York, NY 10965, USA. beyerc@wyeth.com
authors.forename: Carl F
authors.initials: CF
authors.lastname: Beyer
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Hernandez
authors.forename: Danielle
authors.initials: D
authors.lastname: Vitale
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.forename: Carolyn
authors.initials: C
authors.lastname: Discafani
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: James J
authors.initials: JJ
authors.lastname: Gibbons
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006846:Hydrocarbons, Halogenated; D014230:Triazoles; D014404:Tubulin; C521494:cevipabulin