estradiol-3-o-sulfamate and Endometriosis

Steroid sulfatase (STS) converts sulfated hormones to free hormones of importance in hormone-dependent diseases such as breast cancer and endometriosis. Carbohydrate sulfatases degrade complex carbohydrates as part of normal cellular turnover; certain lysosomal storage disorders (LSDs) involve defective processing of sulfated glycosaminoglycans by mutant sulfatases.. Aryl sulfamates have been developed as STS inhibitors, and STX64 and PGL2001 are under evaluation in Phase I and II clinical trials for treatment of endometrial and metastatic breast and prostate cancers and endometriosis. Dual-acting compounds have emerged that are aromatase inhibitors (AIs), selective estrogen receptor antagonists, or inhibitors of microtubule polymerization. Sulfamidase inhibitors as pharmacological chaperones to assist maturation of folding-defective mutants for the treatment of Sanfilippo type A disease are under investigation. Coverage: The patent literature after the mid-1990s.. The failure of STX64 in a Phase II monotherapy clinical trial should not dissuade further investigations in multidrug regimens, particularly in combination with AIs. The recent development of dual-acting compounds may enhance the potential for success in the clinic. Further investigations into aryl sulfamates are required to clarify the molecular mechanism of action; additionally, new reversible sulfatase inhibition concepts are needed for the development of pharmacological chaperones for sulfatase LSDs.

Topics: Animals; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Design; Endometriosis; Enzyme Inhibitors; Estradiol; Female; Humans; Male; Mucopolysaccharidosis III; Patents as Topic; Prostatic Neoplasms; Steryl-Sulfatase; Sulfonic Acids

In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led to steroidal and nonsteroidal drugs in numerous preclinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS, e.g., Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multitargeting agents for hormone-independent tumors, such as the steroidal STX140 and nonsteroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action, and imbues attractive pharmaceutical properties. This Perspective gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status, and how they might develop in the future.

Topics: Animals; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Drug Discovery; Endometriosis; Estrone; Female; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Steryl-Sulfatase; Sulfonic Acids; Tubulin Modulators

Steroid sulfatase (STS) is involved in estrogen biosynthesis and expressed in eutopic and ectopic endometrium of disease-free and endometriosis patients. The present study was designed to investigate its role in endometriosis development.. Human endometrial explants were cultured on inserts for 24 h to assess the effectiveness of an STS inhibitor (STS-I), estradiol-3-O-sulfamate (E2MATE), on STS activity in endometrial tissue. Endometriosis was induced in mice, and E2MATE (or vehicle alone) was given orally for 21 days. Plasma estradiol levels were measured, and STS activity was assessed in murine organs (uterus, liver and leukocytes) and in lesions. Lesion number, weight and size (morphometry) were quantified. Lesion STS and progesterone receptor (PR) expression, proliferation and apoptosis rates were determined by immunohistochemistry.. In vitro, addition of 1 µM E2MATE to the culture medium resulted in decreased STS activity in endometrial explants (P < 0.001). Treatment of mice with E2MATE (1.0 and 0.5 mg/kg) did not modify plasma estradiol levels, but inhibited STS activity in murine uterus (P < 0.05), liver (P < 0.001) and leukocytes (P < 0.001), as well as in induced lesions (P < 0.05). E2MATE reduced lesion weight (P < 0.01) and size (P < 0.05), but had no impact on proliferation or apoptosis rates, nor STS protein expression. Stromal edema was observed in the uterus of animals treated with E2MATE, but not in the stroma of lesions. Increased PR expression was detected in endometriotic lesions (P < 0.001).. E2MATE was shown to effectively inhibit STS activity in endometrial tissue in vitro. In vivo, E2MATE decreased endometriosis development without affecting systemic estradiol levels. Use of STS-I could therefore be of potential interest in endometriosis treatment.

Topics: Animals; Cells, Cultured; Endometriosis; Estradiol; Female; Humans; Mice; Steryl-Sulfatase; Uterus