title: Selective targeting of the stress chaperome as a therapeutic strategy.
abstract: Normal cellular function is maintained by coordinated proteome machinery that performs a vast array of activities. Helping the proteome in such roles is the chaperome, a network of molecular chaperones and folding enzymes. The stressed cell contains, at any time, a complex mixture of chaperome complexes; a majority performs 'housekeeping functions' similarly to non-stressed, normal cells, but a finely-tuned fraction buffers the proteome altered by chronic stress. The stress chaperome is epigenetically distinct from its normal, housekeeping counterpart, providing a basis for its selective targeting by small molecules. We discuss here the development of chaperome inhibitors, and how agents targeting chaperome members in stressed cells are in fact being directed towards chaperome complexes, and their effect is therefore determined by their ability to sample and engage such complexes. A new approach is needed to target and implement chaperome modulators in the investigation of diseases, and we propose that the classical thinking in drug discovery needs adjustment when developing chaperome-targeting drugs.
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Pallav D
authors.initials: PD
authors.lastname: Patel
authors.affiliation: Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chiosisg@mskcc.org.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
mesh_terms: D000818:Animals; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D058990:Molecular Targeted Therapy
chemical_list: D006360:Heat-Shock Proteins; D018832:Molecular Chaperones
keywords: HSP60; HSP70; HSP90; chemical tools; epigenetic regulation; molecular chaperone