Wednesday, November 4, 2009
Ballroom A+B (Camino Real Hotel)
Nuclear receptors are proteins that are responsible for sensing the presence of hormones and other molecules. In response to hormone, these receptors regulate the expression of specific genes in order to control development, homeostasis, and metabolism. When activated by hormone, steroid receptors bind to DNA and regulate genes expression. Steroid receptor maturation and activity requires the ordered assembly of a multimeric chaperone complex. The final stage requires an HSP90 dimer, the p23 cochaperone and one of several immunophilin proteins in order for the receptor to reach a functional state. When the receptor has reached the mature stage it is capable of hormone binding with high affinity. FKBP52 immunophilin preferentially regulates androgen, progesterone, and glucocorticoid receptor-mediated signal transduction. Therefore FKBP52 represents an attractive therapeutic target for the treatment of diseases that are dependent upon a functional hormone signaling pathway. We developed a yeast-based screening assay for use in identifying small molecules that specifically inhibit FKBP52 regulation of androgen receptor function. We then used this assay to screen a diversified compound library containing approximately 2000 compounds of known structure that were selected to have representative diverse chemical structures. These screens resulted in the identification of a candidate compound, MJC13, that potently and specifically inhibit FKBP52-mediated potentiation of receptor function in yeast. We are currently characterizing the inhibitory effects and specificity of inhibition of MJC13 in mammalian cells. Toxicity assays were performed to determine the half maximal inhibitory concentration and the half maximal lethal dose for all cell types used in these studies.