title: Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators.
abstract: Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.
authors.affiliation: The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Hieronymus
authors.forename: Justin
authors.initials: J
authors.lastname: Lamb
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.forename: Xiao P
authors.initials: XP
authors.lastname: Peng
authors.forename: Cristina
authors.initials: C
authors.lastname: Clement
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
authors.forename: Maria
authors.initials: M
authors.lastname: Nieto
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.forename: Srilakshmi M
authors.initials: SM
authors.lastname: Raj
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Maloney
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D015894:Genome, Human; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D036701:Limonins / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000378:metabolism*; D015203:Reproducibility of Results; D014315:Triterpenes / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D036701:Limonins; D053978:Pentacyclic Triterpenes; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014315:Triterpenes; C106014:gedunin; D015741:Metribolone; D066246:ErbB Receptors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; C050414:celastrol; C001277:geldanamycin