title: Heat shock protein 70 inhibitors. 2. 2,5'-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70.
abstract: The discovery and development of heat shock protein 70 (Hsp70) inhibitors is currently a hot topic in cancer. In the preceding paper in this issue ( 10.1021/jm401551n ), we have described structure-activity relationship studies in the first Hsp70 inhibitor class rationally designed to bind to a novel allosteric pocket located in the N-terminal domain of the protein. These ligands contained an acrylamide to take advantage of an active cysteine embedded in the allosteric pocket and acted as covalent protein modifiers upon binding. Here, we perform chemical modifications around the irreversible inhibitor scaffold to demonstrate that covalent modification is not a requirement for activity within this class of compounds. The study identifies derivative 27c, which mimics the biological effects of the irreversible inhibitors at comparable concentrations. Collectively, the back-to-back manuscripts describe the first pharmacophores that favorably and selectively interact with a never explored pocket in Hsp70 and provide a novel blueprint for a cancer-oriented development of Hsp70-directed ligands.
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center , New York, New York 10021, United States.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Kang
authors.forename: Hardik J
authors.initials: HJ
authors.lastname: Patel
authors.forename: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Pallav D
authors.initials: PD
authors.lastname: Patel
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
authors.forename: Yogita
authors.initials: Y
authors.lastname: Patel
authors.forename: Alexander
authors.initials: A
authors.lastname: Gozman
authors.forename: Ronnie
authors.initials: R
authors.lastname: Maharaj
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Clement
authors.forename: Alvin
authors.initials: A
authors.lastname: Lu
authors.forename: Jason C
authors.initials: JC
authors.lastname: Young
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000495:Allosteric Site; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008024:Ligands; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D011743:Pyrimidines