Inhibitors of tubulin assembly identified through screening a compound library.
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.
Morgan
Rachel E
RE
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
Ahn
Sunnoo
S
Nzimiro
Sandra
S
Fotie
Jean
J
Phelps
Mitch A
MA
Cotrill
Jeffrey
J
Yakovich
Adam J
AJ
Sackett
Dan L
DL
Dalton
James T
JT
Werbovetz
Karl A
KA
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
D005456:Fluorescent Dyes; D012235:Rhodamines; D054852:Small Molecule Libraries; D014404:Tubulin; D050257:Tubulin Modulators; C022027:lissamine rhodamine B