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Inhibitors of Tubulin Assembly Identified through Screening a Compound Library
Author(s) -
Morgan Rachel E.,
Ahn Sunjoo,
Nzimiro Sandra,
Fotie Jean,
Phelps Mitch A.,
Cotrill Jeffrey,
Yakovich Adam J.,
Sackett Dan L.,
Dalton James T.,
Werbovetz Karl A.
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2008.00729.x
Subject(s) - tubulin , in vitro , leishmania , cell culture , biology , cancer cell , structure–activity relationship , chemistry , microtubule , biochemistry , cancer , microbiology and biotechnology , genetics , parasite hosting , world wide web , computer science
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 μ m 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 μ m ). This compound was also toxic to several cancer cell lines with IC 50 values in the region of 1 μ m . 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 μ m ). 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 μ m .