Identification of a small molecule that induces mitotic arrest using a simplified high-content screening assay and data analysis method.
High-content screening has emerged as a new and powerful technique for identifying small-molecule modulators of mammalian cell biology. The authors describe the development and execution of a high-content screen to identify small molecules that induce mitotic arrest in mammalian cancer cells. Many widely used chemotherapeutics, such as Taxol and vinblastine, induce mitotic arrest, and the creation of new drugs that also induce mitotic arrest may have tremendous therapeutic value. In their screen, the authors employed a simple DNA stain (DAPI) and a sensitive nonparametric statistical test to identify compounds from an internal collection of approximately 13,000 high-quality lead-like small molecules. Subsequent analysis of 1 active compound indicated that it induces mitotic arrest, assessed using a high-content phosphohistone H3 detection assay, and caused cell proliferation defects in multiple cancer cell lines. The active compound, a quinazolinone originating from a natural product-like subset of the screened compounds, is active in cells at approximately 500 nM and appears to act by inhibiting the polymerization of tubulin.
Wilson
Christopher J
CJ
Department of Chemical Genomics, ArQule Incorporated, Woburn, MA, USA. chris_wilson@alum.mit.edu
Si
Ying
Y
Thompsons
Craig M
CM
Smellie
Andrew
A
Ashwell
Mark A
MA
Liu
Ji-Feng
JF
Ye
Ping
P
Yohannes
Daniel
D
Ng
Shi-Chung
SC
D001681:Biological Assay; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012107:Research Design; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002843:Chromatin; D011799:Quinazolines; D014404:Tubulin; D017239:Paclitaxel