title: Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94.
abstract: 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.
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Hardik J
authors.initials: HJ
authors.lastname: Patel
authors.affiliation: †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.
authors.forename: Pallav D
authors.initials: PD
authors.lastname: Patel
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Pengrong
authors.initials: P
authors.lastname: Yan
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Weilin
authors.initials: W
authors.lastname: Sun
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Smit K
authors.initials: SK
authors.lastname: Shah
authors.affiliation: §Department of Pharmacology and Anesthesiology, University of Padua, Largo E. Meneghetti 2, 35131, Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tramentozzi
authors.affiliation: ∥Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14850, United States.
authors.forename: James
authors.initials: J
authors.lastname: Brooks
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bolaender
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Liza
authors.initials: L
authors.lastname: Shrestha
authors.affiliation: ‡Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stephani
authors.affiliation: §Department of Pharmacology and Anesthesiology, University of Padua, Largo E. Meneghetti 2, 35131, Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Finotti
authors.affiliation: ∥Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14850, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Leifer
authors.affiliation: ⊥Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina United States.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: #Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, United States.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Gewirth
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: †Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, New York 10021, United States.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007335:Insulin-Like Growth Factor II; D008024:Ligands; D008562:Membrane Glycoproteins; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C000599956:8-((3,5-dichlorophenyl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine; C053387:endoplasmin