The receptor specificity displayed by FKBP52 and the receptor-specific phenotypes observed in the fkbp52
-deficient mice have established FKBP52 as an attractive therapeutic target for the treatment of hormone-dependent diseases. Given the receptor-specific phenotypes observed in the mice one would predict a role for FKBP52 in androgen-dependent diseases; most notably prostate cancer. Indeed, FKBP52 is up-regulated in prostate needle biopsies [29
] and our early FKBP52-specific drug candidates have shown great promise at inhibiting prostate cancer cell proliferation and androgen-dependent gene expression (unpublished observations).
Given the role of FKBP52 in reproductive development and success [2
] FKBP52 could serve as a target for contraceptive drugs. FKBP52 is critical for embryo implantation in females [12
] and could reasonably serve as a target for female contraception. Although fkbp52-deficient male mice have normal testis that produce viable sperm [2
], the sperm do have reduced motility [11
]. It is not clear if the testis in the mice have high enough testosterone levels produced locally that compensate for reduced AR activity in the absence of FKBP52, or if there is some factor present in the testis that can compensate for the loss of FKBP52. Thus, more studies to resolve these issues are needed, but FKBP52 may also serve as a target for male contraceptives.
Although FKBP52 can be found in association with estrogen receptor (ER)-chaperone complexes, an FKBP52-mediated functional effect on ER signaling has not been observed in cellular assays. However, FKBP52 is over-expressed in breast tumors [30
] and is up-regulated transcriptionally and post-transcriptionally by estrogen [31
]. Exposure to the pure estrogen antagonist ICI182,780 (fulvestrant) prevents this estrogen-mediated increase. A recent study has found that the FKBP52 gene is methylated in ER-negative MDA-MB-231, but not in ER-positive MCF7 cells, suggesting that repression of FKBP52 may, itself, affect ER expression [32
]. Thus, early studies implicate FKBP52 as a potential target for breast cancer, although more investigations into the role of FKBP52 in breast cancer are needed.
The current drug and drug candidates targeting receptor regulatory proteins lack sufficient specificity, and drugs targeting the receptor hormone binding pockets often lack efficacy in late stage disease. illustrates known and predicted interactions in addition to known and possible therapeutic targeting strategies. Geldanamycin and its analogs, for example, exhibit potent antitumor activity by inhibiting Hsp90 interaction with client proteins, leading to increased client protein degradation. However, these drugs could potentially affect any Hsp90 client protein leading to adverse side effects, although the Hsp90 inhibitors do preferentially target cancer cells [reviewed in 33]. In addition, geldanamycin has been completely ineffective in prostate cancer.
Immunophilins are targets of the immunosuppressant macrolide FK506 (Tacrolimus), which is clinically used after organ transplantation [review in 34]. FK506 is a large molecule that binds the PPIase pocket and protrudes out, forming a false interaction surface that binds with high affinity to calcineurin resulting in immunosuppression [35
]. FK506 does not discriminate among the FKBP family members and immunosuppression is not a desirable side effect for an anti-cancer drug. Although FK506 binding to FKBP52 is not immunosuppressive, it does inhibit FKBP52-mediated potentiation of steroid receptor function and inhibits prostate cancer cell proliferation [36
]. This not only demonstrates that FKBP52 is a “druggable” protein, but also provides proof of principle for the targeting of FKBP52 for the treatment of prostate cancer. FK506 could be used as a scaffold to design a large molecule that protrudes out of the PPIase pocket and interferes with FKBP52 proline-rich loop interactions, but that does not share the parent compound's affinity for calcineunin and its immunosuppressive effect. However, such a molecule may not be able to discriminate between the FKBPs given the conservation of the PPIase pocket. Considering the highly conserved nature of the TPR domain, especially among the FKBP family members, there are also concerns about targeting the FKBP52 TPR domain as well. The recent work by Riggs et al
] suggests that blocking proline-rich loop interactions is potentially a highly specific therapeutic strategy to inhibit receptor function. It is likely that small molecule inhibitors specific for the FKBP52 FK1 domain, and perhaps even the proline-rich loop, can be developed. Finally, threonine 143 within the FKBP52 FK Linker () that links the FK1 and FK2 domains is phosphorylated by casein kinase 2 and this phosphorylation event was demonstrated to reorient the entire FK1 domain leading to a loss of FKBP52 function [37
]. Thus, targeting the FKBP52 FK Linker may be a viable option. Our laboratory is currently pursuing multiple strategies for the development of FKBP52-specific inhibitors.