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

Ciorsdaidh A Watts; Frances M Richards; Andreas Bender; Peter J Bond; Oliver Korb; Oliver Kern; Michelle Riddick; Paul Owen; Rebecca M Myers; Jordan Raff; Fanni Gergely; Duncan I Jodrell; Steven V Ley

doi:10.1016/j.chembiol.2013.09.012

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

Chem Biol. 2013 Nov 21;20(11):1399-410. doi: 10.1016/j.chembiol.2013.09.012. Epub 2013 Oct 24.

Authors

Ciorsdaidh A Watts¹, Frances M Richards, Andreas Bender, Peter J Bond, Oliver Korb, Oliver Kern, Michelle Riddick, Paul Owen, Rebecca M Myers, Jordan Raff, Fanni Gergely, Duncan I Jodrell, Steven V Ley

Affiliation

¹ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Centrosome / drug effects*
Centrosome / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Kinesins / antagonists & inhibitors*
Kinesins / metabolism
MCF-7 Cells
Models, Molecular
Molecular Structure
Phenylalanine / analogs & derivatives*
Phenylalanine / chemical synthesis
Phenylalanine / chemistry
Phenylalanine / pharmacology
Structure-Activity Relationship
ortho-Aminobenzoates / chemical synthesis
ortho-Aminobenzoates / chemistry
ortho-Aminobenzoates / pharmacology*

Substances

Antineoplastic Agents
CW069 compound
Enzyme Inhibitors
ortho-Aminobenzoates
Phenylalanine
Kinesins

Abstract

Publication types

MeSH terms

Substances

Grants and funding