Inhibitors of tubulin assembly identified through screening a compound library

Rachel E. Morgan, Sunjoo Ahn, Sandra Nzimiro, Jean Fotie, Mitch A. Phelps, Jeffrey Cotrill, Adam J. Yakovich, Dan L. Sackett, James T. Dalton, Karl A. Werbovetz

    Research output: Contribution to journalArticlepeer-review

    11 Citations (Scopus)

    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 IC50 of 13µM 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 (IC50 = 5.0µM). This compound was also toxic to several cancer cell lines with IC50 values in the region of 1µM. Subsequent testing of analogues of 8 contained within the library identified two compounds with greater potency against mammalian tubulin (IC50 values of 1.1 and 2.8µM). The more potent antitubulin agent also showed promising activity against cancer cell lines in vitro, with IC50 values ranging from 0.18 to 0.73µM.

    Original languageEnglish
    Pages (from-to)513-524
    Number of pages12
    JournalChemical Biology & Drug Design
    Volume72
    Issue number6
    DOIs
    Publication statusPublished - Dec 2008

    Keywords

    • Animals
    • Cercopithecus aethiops
    • Drug Screening Assays, Antitumor
    • Flow Cytometry
    • Fluorescent Dyes
    • Humans
    • Inhibitory Concentration 50
    • Leishmania
    • Rhodamines
    • Small Molecule Libraries
    • Structure-Activity Relationship
    • Swine
    • Tubulin
    • Tubulin Modulators
    • Tumor Cells, Cultured
    • Vero Cells

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