gedunin and celastrol

Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA.

Topics: Benzoquinones; Cell Line, Tumor; Chromatography, Affinity; HSP90 Heat-Shock Proteins; Humans; Hydrolysis; Immunoprecipitation; Lactams, Macrocyclic; Models, Molecular; Novobiocin; Pentacyclic Triterpenes; Triterpenes

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.

Topics: Antibiotics, Antineoplastic; Benzoquinones; Biomarkers, Tumor; Cell Culture Techniques; Cell Line; Cell Line, Tumor; Cell Survival; ErbB Receptors; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; Gene Expression; Gene Expression Profiling; Genome, Human; HSP90 Heat-Shock Proteins; Humans; Inhibitory Concentration 50; Lactams, Macrocyclic; Limonins; Male; Metribolone; Pentacyclic Triterpenes; Prostatic Neoplasms; Receptors, Androgen; Reproducibility of Results; RNA, Messenger; Triterpenes