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

doi:10.1111/j.1747-0285.2008.00729.x

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 journal › Article › peer-review

18 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 language	English
Pages (from-to)	513-524
Number of pages	12
Journal	Chemical Biology & Drug Design
Volume	72
Issue number	6
DOIs	https://doi.org/10.1111/j.1747-0285.2008.00729.x
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/j.1747-0285.2008.00729.x

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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 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.",

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

year = "2008",

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doi = "10.1111/j.1747-0285.2008.00729.x",

language = "English",

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AU - Morgan, Rachel E.

AU - Ahn, Sunjoo

AU - Nzimiro, Sandra

AU - Fotie, Jean

AU - Phelps, Mitch A.

AU - Cotrill, Jeffrey

AU - Yakovich, Adam J.

AU - Sackett, Dan L.

AU - Dalton, James T.

AU - Werbovetz, Karl A.

PY - 2008/12

Y1 - 2008/12

N2 - 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.

AB - 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.

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KW - Inhibitory Concentration 50

KW - Leishmania

KW - Rhodamines

KW - Small Molecule Libraries

KW - Structure-Activity Relationship

KW - Swine

KW - Tubulin

KW - Tubulin Modulators

KW - Tumor Cells, Cultured

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Inhibitors of tubulin assembly identified through screening a compound library

Abstract

Keywords

UN SDGs

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