Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94

J Med Chem. 2015 May 14;58(9):3922-43. doi: 10.1021/acs.jmedchem.5b00197. Epub 2015 Apr 22.


Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / pharmacokinetics
  • Adenine / pharmacology
  • Allosteric Site
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Differentiation
  • Cell Line
  • Cell Line, Tumor
  • Endoplasmic Reticulum / metabolism*
  • Female
  • HSP90 Heat-Shock Proteins / metabolism*
  • Insulin-Like Growth Factor II / metabolism
  • Ligands
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / metabolism
  • Mice, Nude
  • Molecular Docking Simulation
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Protein Binding
  • Purines / chemistry*
  • Purines / pharmacokinetics
  • Purines / pharmacology
  • Receptor, ErbB-2 / metabolism
  • Structure-Activity Relationship
  • Tissue Distribution
  • Toll-Like Receptor 9 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis


  • 8-((3,5-dichlorophenyl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine
  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Ligands
  • Membrane Glycoproteins
  • Purines
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha
  • endoplasmin
  • Insulin-Like Growth Factor II
  • Receptor, ErbB-2
  • Adenine