2. Academic Validation
  3. Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70

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

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.

Figures
Products