2-methoxyestradiol-3-17-o-o-bis(sulfamate) and irosustat

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

The past few years have seen an increase in the reported incidence of endometrial carcinoma, one of the most frequently diagnosed malignancies of the female genital tract. Estrogen production is vital for the mitogenesis of endometrial tumors. Inhibition of steroid sulfatase (STS), an enzyme responsible for the synthesis of steroids with estrogenic properties, may represent a novel therapeutic target for this type of cancer. This study investigates the effects of STX64 (also known as 667Coumate and BN83495) and STX213, two potent STS inhibitors, on hormone-dependent endometrial cancer cell growth in vivo. When tested in intact mice with endometrial cancer xenografts, STX64 had limited effect on tumor growth. In contrast, the microtubule disruptor STX140 reduced tumor growth by 55%. In a hormone-dependent endometrial xenograft model in ovariectomized mice, both STX64 and STX213 given orally, daily at 1 mg/kg significantly inhibited tumor growth by 48 and 67%, respectively. However, when given orally at 1 mg/kg once weekly, only STX213 still inhibited tumor proliferation. At a higher dose of STX64 (10 mg/kg, orally, daily), a greater tumor growth inhibition of 59% was observed. Liver and tumor STS activity was completely inhibited in all daily treatment groups. Plasma estradiol (E2) levels were also significantly decreased. A significant correlation was observed between plasma E2 concentrations and STS activity, indicating the importance of circulating E2 on tumor growth. This novel study demonstrates for the first time that STS inhibitors are potent inhibitors of endometrial cancer growth in nude mice.

Topics: Animals; Antineoplastic Agents, Hormonal; Azasteroids; Carcinoma; Cell Proliferation; Coumarins; Endometrial Neoplasms; Estradiol; Estrenes; Female; Humans; Mice; Mice, Nude; Models, Biological; Neoplasms, Hormone-Dependent; Ovariectomy; Steryl-Sulfatase; Sulfonamides; Sulfonic Acids; Tumor Cells, Cultured; Xenograft Model Antitumor Assays