title: Inhibitors of tubulin assembly identified through screening a compound library.
abstract: Tubulin is the proposed target for drugs against cancer and helminths and is also a validated target in kinetoplastid parasites. With the aim of identifying new lead compounds against Leishmania sp., tubulin isolated from L. tarentolae was used to screen a 10 000 compound library. One compound, Chembridge No. 7992831 (5), displayed an IC(50) of 13 microm against Leishmania tubulin in an in vitro assembly assay and showed a greater than threefold selectivity over mammalian tubulin. Another compound, Chembridge No. 9067250 (8), exhibited good activity against mammalian tubulin (IC(50) = 5.0 microm). This compound was also toxic to several cancer cell lines with IC(50) values in the region of 1 microm. Subsequent testing of analogues of 8 contained within the library identified two compounds with greater potency against mammalian tubulin (IC(50) values of 1.1 and 2.8 microm). The more potent antitubulin agent also showed promising activity against cancer cell lines in vitro, with IC(50) values ranging from 0.18 to 0.73 microm.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA. R.E.Morgan@dundee.ac.uk
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Morgan
authors.forename: Sunnoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Sandra
authors.initials: S
authors.lastname: Nzimiro
authors.forename: Jean
authors.initials: J
authors.lastname: Fotie
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cotrill
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Yakovich
authors.forename: Dan L
authors.initials: DL
authors.lastname: Sackett
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects; D012235:Rhodamines / Q000032:analysis / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013552:Swine; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014709:Vero Cells
chemical_list: D005456:Fluorescent Dyes; D012235:Rhodamines; D054852:Small Molecule Libraries; D014404:Tubulin; D050257:Tubulin Modulators; C022027:lissamine rhodamine B