Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes

Watts, C. A. et al. (2013) Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes. Chemistry and Biology, 20(11), pp. 1399-1410. (doi: 10.1016/j.chembiol.2013.09.012) (PMID:24210220) (PMCID:PMC3898838)

[img]
Preview
Text
109322.pdf - Published Version

3MB

Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Watts, Dr Ciorsdaidh
Authors: Watts, C. A., Richards, F. M., Bender, A., Bond, P. J., Korb, O., Kern, O., Riddick, M., Owen, P., Myers, R. M., Raff, J., Gergely, F., Jodrell, D. I., and Ley, S. V.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Chemistry and Biology
Publisher:Cell Press
ISSN:1074-5521
ISSN (Online):1879-1301
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Chemistry & Biology 20(11):1399-1410
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record