title: The anticancer drug AUY922 generates a proteomics fingerprint that is highly conserved among structurally diverse Hsp90 inhibitors.
abstract: AUY922 is a potent synthetic Hsp90 antagonist that is moving steadily through clinical trials against a small range of cancers. To identify protein markers that might measure the drug's effects, and to gain understanding of mechanisms by which AUY922 might inhibit the proliferation of leukemia cells, we characterized AUY922's impacts on the proteomes of cultured Jurkat cells. We describe a robust and readily assayed proteomics fingerprint that AUY922 shares with the flagship Hsp90 inhibitors 17-DMAG and radicicol. We also extend our proteomics findings, demonstrating that an unrelated antagonist of protein folding potentiates the antiproliferative effects of AUY922. Results provide a set of candidate biomarkers for responses to AUY922 in leukemia cells and suggest new modalities for enhancing AUY922's anticancer activities.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma 74078, USA.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Voruganti
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Lacroix
authors.forename: Chelsea N
authors.initials: CN
authors.lastname: Rogers
authors.forename: Janet
authors.initials: J
authors.lastname: Rogers
authors.forename: Robert L
authors.initials: RL
authors.lastname: Matts
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hartson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding / Q000187:drug effects; D020543:Proteome / Q000032:analysis*; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D018942:Macrolides; D020543:Proteome; D012118:Resorcinols; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin