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

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

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†Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
‡Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, United States.
§Department of Pharmacology and Anesthesiology, University of Padua, Largo E. Meneghetti 2, 35131, Padua, Italy.
∥Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14850, United States.
⊥Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina United States.
#Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, United States.


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.

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