Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

  • J Med Chem. 2016 May 26;59(10):4625-36. doi: 10.1021/acs.jmedchem.5b02001.
Matthew D Cheeseman  1 ,  Isaac M Westwood  1  2 ,  Olivier Barbeau  1 ,  Martin Rowlands  1 ,  Sarah Dobson  1  2 ,  Alan M Jones  1 ,  Fiona Jeganathan  1 ,  Rosemary Burke  1 ,  Nadia Kadi  1 ,  Paul Workman  1 ,  Ian Collins  1 ,  Rob L M van Montfort  1  2 ,  Keith Jones  1
Affiliations
  • 1. Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , London SW7 3RP, U.K.
  • 2. Division of Structural Biology, The Institute of Cancer Research , London SW7 3RP, U.K.
PMID: 27119979 DOI: 10.1021/acs.jmedchem.5b02001
Abstract

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

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