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Identification of a Small Molecule That Induces Mitotic Arrest Using a Simplified High-Content Screening Assay and Data Analysis Method

Department of Chemical Genomics, ArQule Incorporated, Woburn, MA

Ying Si

Department of Chemical Genomics, ArQule Incorporated, Woburn, MAchris_wilson{at}alum.mit.edu

Craig M. Thompsons

Department of Chemical Genomics, ArQule Incorporated, Woburn, MA; Cell Signaling Technologies Incorporated, Beverly, MA

Andrew Smellie

Department of Informatics and Modeling, ArQule Incorporated, Woburn, MA

Mark A. Ashwell

Department of Drug Discovery Chemistry, ArQule Incorporated, Woburn, MA

Ji-Feng Liu

Ping Ye

Daniel Yohannes

Department of Chemistry, ArQule Incorporated, Woburn, MA

Shi-Chung Ng

Department of Chemical Genomics, ArQule Incorporated, Woburn, MA

High-content screening has emerged as a newand powerful technique for identifying small-molecule modulators ofmammalian cell biology. The authors describe the development and execution of a high-content screen to identify smallmolecules 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 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 inmultiple cancer cell lines. The active compound, a quinazolinone originating from a natural product-like subset of the screened compounds, is active in cells at 500nMand appears to act by inhibiting the polymerization of tubulin.

Key Words: high-content screening • image-based screening • mitotic arrest • tubulin

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