title: Therapeutic Targeting of the FKBP52 Co-Chaperone in Steroid Hormone Receptor-Regulated Physiology and Disease.
abstract: Steroid hormone receptors are ligand-dependent transcription factors that require the dynamic, ordered assembly of multimeric chaperone complexes to reach a functional conformation. Heat shock protein (Hsp) 70 and Hsp90 serve as the central chaperones that mediate this process in conjunction with a variety of co-chaperones. Many of these cochaperones represent potential therapeutic targets for the disruption of Hsp90 client protein function. FKBP52 is an Hsp90-associated co-chaperone that has emerged as a promising therapeutic candidate due to its functional specificity for a small subset of Hsp90 client proteins including androgen (AR), glucocorticoid (GR), and progesterone (PR) receptors. Given its Hsp90-client protein specificity, the targeting of FKBP52 should be more specific and less toxic than the Hsp90- targeting drugs. Additionally, the fkbp52-deficient mice display specific phenotypes related to androgen, progesterone, and glucocorticoid insensitivity suggesting minimal off-target effects. Finally, the fact that FKBP52 is already a validated target of the clinically approved immunosuppressive drug, FK506 (Tacrolimus), indicates that FKBP52 is a "druggable" protein. Thus, the development of FKBP52-specific small molecule inhibitors is predicted to be a highly targeted strategy with potential for the treatment of any disease that is dependent on a functional AR, GR, and/or PR signaling pathway. Much progress has been made in understanding the residues and domains critical for FKBP52 function. The proline-rich loop overhanging the FKBP52 FK1 catalytic domain is functionally important and likely represents an interaction surface within the receptor-chaperone complex. Thus, the targeting of FKBP52 proline-rich loop interactions is the most attractive therapeutic approach to disrupt FKBP52 regulation of receptor activity in steroid hormone receptor-dependent physiology and disease.
authors.forename: Naihsuan C
authors.initials: NC
authors.lastname: Guy
authors.forename: Yenni A
authors.initials: YA
authors.lastname: Garcia
authors.affiliation: Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave. El Paso, TX 79968. USA. mbcox@utep.edu.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
mesh_terms: D000818:Animals; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4