The Hsp90 binding protein FKBP52, through interactions with the steroid hormone receptors, plays important physiological and potentially pathological roles in mammals. FKBP52 specifically regulates the androgen, progesterone and glucocorticoid receptors. Thus, FKBP52 represents an attractive therapeutic target for the treatment of hormone-dependent cancers such as prostate cancer. We have made progress in understanding the regions of functional importance on FKBP52, but we still do not know where the FKBP52 interaction site is on the receptors. The main hypothesis to be tested in this proposal is that FKBP52 potentiation of receptor function occurs through direct contacts between the FKBP52 FK1 domain and the receptor ligand binding domain leading to an enhancement of hormone binding. The dynamic nature by which the receptors achieve their hormone bound conformations to which FKBP52 associates makes it impractical to use a simple purified protein system. Thus, we must use more sophisticated approaches to analyze direct interactions between the steroid receptors and associated cochaperones. Each of the specific aims detailed below are independent from each other, but are all aimed at proving the proposed interaction between the FKBP52 FK1 domain and the receptor LBD and targeting that interaction with small molecule inhibitors. The long term goal of this project is the development of novel drugs for the treatment of hormone-dependent cancers. Towards this goal our immediate specific aims are:
Aim #1 : Use a previously validated androgen receptor-mediated reporter assay in yeast to identify random mutations within the receptor that alter the receptor's response to the FKBP proteins.
Aim #2 : Use directed photo affinity labeling of a cysteine-lacking FKBP52 mutant in combination with cross linking/mass spectrometry to identify and characterize the FKBP52-receptor interaction site.
Aim #3 : Screen compound libraries for selective FKBP52 inhibitors and characterize the specificity of inhibition and FKBP52 binding sites. We have identified two selective FKBP52 inhibitors to date. ? ? ?
|Liang, Su; Bian, Xiaomei; Liang, Dong et al. (2016) Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer. Pharm Dev Technol 21:121-6|
|Storer Samaniego, Cheryl; Suh, Ji Ho; Chattopadhyay, Arundhati et al. (2015) The FKBP52 Cochaperone Acts in Synergy with ?-Catenin to Potentiate Androgen Receptor Signaling. PLoS One 10:e0134015|
|Erlejman, Alejandra G; Lagadari, Mariana; Harris, Diondra C et al. (2014) Molecular chaperone activity and biological regulatory actions of the TPR-domain immunophilins FKBP51 and FKBP52. Curr Protein Pept Sci 15:205-15|
|Liang, Su; Bian, Xiaomei; Sivils, Jeffrey et al. (2014) Quantification of a New Anti-Cancer Molecule MJC13 Using a Rapid, Sensitive, and Reliable Liquid Chromatography-Tandem Mass Spectrometry Method. Am J Mod Chromatogr 1:1-11|
|Paul, Atanu; Garcia, Yenni A; Zierer, Bettina et al. (2014) The cochaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) demonstrates regulatory specificity for the androgen, glucocorticoid, and progesterone receptors. J Biol Chem 289:15297-308|
|Shafi, Ayesha A; Cox, Marc B; Weigel, Nancy L (2013) Androgen receptor splice variants are resistant to inhibitors of Hsp90 and FKBP52, which alter androgen receptor activity and expression. Steroids 78:548-54|
|Sivils, Jeffrey C; Storer, Cheryl L; Galigniana, Mario D et al. (2011) Regulation of steroid hormone receptor function by the 52-kDa FK506-binding protein (FKBP52). Curr Opin Pharmacol 11:314-9|
|Cox, Marc B; Johnson, Jill L (2011) The role of p23, Hop, immunophilins, and other co-chaperones in regulating Hsp90 function. Methods Mol Biol 787:45-66|
|De Leon, Johanny Tonos; Iwai, Aki; Feau, Clementine et al. (2011) Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A 108:11878-83|
|Storer, Cheryl L; Dickey, Chad A; Galigniana, Mario D et al. (2011) FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab 22:481-90|
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