Pharmaceutical compositions which inhibit FKBP52-mediated regulation of androgen receptor function and methods of using same
Inventors
Neckers, Leonard M. • Cox, Marc B. • Neckers, Jane B. • Kim, Yeong Sang • Iwai, Aki • Ning, Yangmin • Kugelman-Tonos, Johanny • Balsiger, Heather A. • Fletterick, Robert
Assignees
University of Texas System • University of California San Diego UCSD • US Department of Health and Human Services
Publication Number
US-9782399-B2
Publication Date
2017-10-10
Expiration Date
2030-09-14
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Pharmaceutical compositions that bind to a predicted FK506 Binding Protein 52 (FKBP52) interaction surface on the androgen receptor hormone binding domain, otherwise known as FKBP52 Targeting Agents (FTAs) are provided. These compositions of the present invention are found to specifically recognize the FKBP52 regulatory surface on the androgen receptor and inhibit FKBP52 from functionally interacting with the androgen receptor. Compositions comprising the pharmaceutical composition, as well as methods of use, treatment and screening are also provided.
Core Innovation
The invention provides pharmaceutical compositions that specifically bind to a predicted FK506 Binding Protein 52 (FKBP52) interaction surface on the androgen receptor (AR) hormone binding domain, referred to as FKBP52 Targeting Agents (FTAs). These compositions inhibit FKBP52 from functionally interacting with the androgen receptor, thus modulating steroid receptor activity specifically enhanced by FKBP52, including AR, GR, and PR function.
The problem being solved is the need for selective AR modulators that inhibit AR function non-competitively, without acting as competitive agonists or antagonists at the hormone binding pocket. Previous compounds inhibited AR function by binding the BF3 surface or competing with endogenous hormone binding, but compounds selectively inhibiting FKBP52-enhanced AR function at lower effective concentrations than those acting on AR alone were lacking.
The invention addresses this problem by identifying a distinct FKBP52 regulatory surface on the AR hormone binding domain, and providing FTAs that inhibit FKBP52-enhanced receptor activity without binding the BF3 region or competing with endogenous hormone binding. Methods for treatment of hormone-related diseases, assays for screening such compounds, and compositions comprising FTAs with pharmaceutically acceptable carriers are also provided.
Claims Coverage
The patent contains one independent claim directed to a method for reducing benign prostatic hyperplasia using specific compounds. The claim focuses on inventive features related to compounds, combinations, and administration methods.
Selective inhibition of benign prostatic hyperplasia using specific compounds
A method of reducing, suppressing, or inhibiting benign prostatic hyperplasia (BPH) in a male mammal by administering pharmaceutical compositions comprising compounds selected from a specified group represented by structural formulas included in the patent.
Combination therapy with anti-androgenic compounds and LH-RH agonists
The pharmaceutical composition can further comprise one or more anti-androgenic compounds and/or luteinizing hormone-releasing hormone (LH-RH) agonists to enhance therapeutic effects for BPH treatment.
Use of specific anti-androgenic compounds in combination
The anti-androgenic compounds used in combination can include bicalutamide, nilutamide, and 5-alpha-reductase inhibitors for effective treatment.
Specific 5-alpha-reductase inhibitors for combined therapy
The 5-alpha-reductase inhibitors include MK-906, 17-β-N,N-diethylcarbamoyl-4-methyl-4-aza-5-α-androstan-3-one, 4-azasteroid, 6-methylene-4-pregnene-3,20-dione, and 4-methyl-3-oxo-4-aza-5-α-pregnane-30(s) carboxylate as part of combined therapeutic regimens.
Administration of defined compounds or their pharmaceutically acceptable derivatives
Compounds comprising specific structures (referred to as compound 1, compound 4, or others with provided structural formulas) or their pharmaceutically acceptable salts, solvates or stereoisomers are administered to the mammal in effective amounts.
Further administration of compounds structurally related to initial compounds
Additional administration of structurally related compounds as defined by the sequential claims enhances or complements the therapeutic method for treating BPH.
The independent claim provides a method for treating benign prostatic hyperplasia by administering pharmaceutical compositions containing specific compounds that inhibit FKBP52-mediated androgen receptor function, alone or in combination with established anti-androgenic agents and LH-RH agonists. The claim emphasizes the use of structurally characterized compounds and their pharmaceutically acceptable forms in the treatment.
Stated Advantages
The compounds specifically inhibit FKBP52-enhanced steroid receptor activity, allowing targeted modulation of AR, GR, and PR function.
The FTAs act non-competitively, avoiding disruption of endogenous hormone binding, providing a novel approach to AR inhibition.
The compositions are effective at concentrations lower than those required for inhibition of AR function in the absence of FKBP52, enhancing therapeutic specificity and potency.
The invention enables treatment of multiple hormone-related medical conditions, including prostate cancer, benign prostatic hyperplasia, type 2 diabetes, metabolic syndrome, and fertility suppression in males and females.
Documented Applications
Treatment of prostate cancer in mammals by administering pharmaceutical compositions comprising FTAs alone or in combination with chemotherapeutic and/or anti-androgenic agents such as bicalutamide, nilutamide, flutamide, finasteride, and ketoconazole.
Treatment of benign prostatic hyperplasia (BPH) in mammals with FTAs, optionally combined with anti-androgenic agents and 5-alpha-reductase inhibitors including finasteride and ketoconazole.
Treatment of non-insulin dependent diabetes (type 2) and metabolic syndrome by administering FTAs, alone or with additional therapeutic agents such as sulfonylureas, metglitinides, biguanides, thiazolidinediones, and DPP-4 inhibitors.
Suppression or inhibition of fertility in male mammals by administering FTAs to inhibit spermatogenesis.
Suppression or inhibition of fertility in female mammals by administering FTAs to inhibit pregnancy.
Screening for novel FTAs using a mammalian model system comprising FKBP52-deficient murine embryonic fibroblasts transfected with AR and reporter constructs to evaluate inhibition of FKBP52-enhanced AR activity.
Interested in licensing this patent?