title: Heat shock protein 70 inhibitors. 1. 2,5'-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders to an allosteric site on heat shock protein 70.
abstract: Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure-activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5'-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.
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: Yanlong
authors.initials: Y
authors.lastname: Kang
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.forename: Hardik J
authors.initials: HJ
authors.lastname: Patel
authors.forename: Pallav D
authors.initials: PD
authors.lastname: Patel
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
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: Maulik R
authors.initials: MR
authors.lastname: Patel
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: Jason C
authors.initials: JC
authors.lastname: Young
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000495:Allosteric Site; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008024:Ligands; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D011743:Pyrimidines