期刊
CURRENT MOLECULAR PHARMACOLOGY
卷 9, 期 2, 页码 109-125出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1874467208666150519114115
关键词
Androgen receptor; FKBP4; FKBP52; glucocorticoid receptor; immunophilin; progesterone receptor; prostate cancer; steroid hormone receptor
资金
- National Institute on Minority Health and Health Disparities [2G12MD007592]
- National Institutes of Health
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP110444-P2]
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 Hsp90targeting 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.
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