Guy Naihsuan C, Garcia Yenni A, Cox Marc B
Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, 500 W. University Ave. El Paso, TX 79968. USA.
Curr Mol Pharmacol. 2015;9(2):109-25. doi: 10.2174/1874467208666150519114115.
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.
类固醇激素受体是依赖配体的转录因子，需要多聚体伴侣复合物进行动态、有序组装才能达到功能构象。热休克蛋白（Hsp）70和Hsp90作为核心伴侣蛋白，与多种共伴侣蛋白共同介导这一过程。其中许多共伴侣蛋白是破坏Hsp90客户蛋白功能的潜在治疗靶点。FKBP52是一种与Hsp90相关的共伴侣蛋白，由于其对包括雄激素（AR）、糖皮质激素（GR）和孕激素（PR）受体在内的一小部分Hsp90客户蛋白具有功能特异性，已成为一种有前景的治疗候选物。鉴于其对Hsp90客户蛋白的特异性，靶向FKBP52应该比靶向Hsp90的药物更具特异性且毒性更小。此外，fkbp52基因缺陷小鼠表现出与雄激素、孕激素和糖皮质激素不敏感相关的特定表型，表明脱靶效应最小。最后，FKBP52已经是临床批准的免疫抑制药物FK506（他克莫司）的一个经过验证的靶点，这一事实表明FKBP52是一种“可成药”蛋白。因此，预计开发FKBP52特异性小分子抑制剂将是一种高度靶向的策略，有可能用于治疗任何依赖功能性AR、GR和/或PR信号通路的疾病。在理解对FKBP52功能至关重要的残基和结构域方面已经取得了很大进展。FKBP52 FK1催化结构域上方富含脯氨酸的环在功能上很重要，可能代表受体-伴侣复合物内的一个相互作用表面。因此，靶向FKBP52富含脯氨酸环的相互作用是破坏类固醇激素受体依赖性生理和疾病中FKBP52对受体活性调节的最有吸引力的治疗方法。
