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Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics.

Original publication

DOI

10.1016/j.chembiol.2013.09.012

Type

Journal article

Journal

Chem Biol

Publication Date

21/11/2013

Volume

20

Pages

1399 - 1410

Keywords

Allosteric Regulation, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Centrosome, Dose-Response Relationship, Drug, Drug Design, Drug Screening Assays, Antitumor, Enzyme Inhibitors, HeLa Cells, Humans, Kinesin, MCF-7 Cells, Models, Molecular, Molecular Structure, Phenylalanine, Structure-Activity Relationship, ortho-Aminobenzoates