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.


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*


  • Antineoplastic Agents
  • CW069 compound
  • Enzyme Inhibitors
  • ortho-Aminobenzoates
  • Phenylalanine
  • Kinesins