estradiol-3-o-sulfamate and Breast-Neoplasms

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

The anticancer activities and SARs of estradiol-17-O-sulfamates and estradiol 3,17-O,O-bis-sulfamates (E2bisMATEs) as steroid sulfatase (STS) inhibitors and antiproliferative agents are discussed. Estradiol 3,17-O,O-bis-sulfamates 20 and 21, in contrast to the 17-O-monosulfamate 11, proved to be excellent STS inhibitors. 2-Substituted E2bisMATEs 21 and 23 additionally exhibited potent antiproliferative activity with mean graph midpoint values of 18-87 nM in the NCI 60-cell-line panel. 21 Exhibited antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model, and 23 dosed p.o. caused marked growth inhibition in a nude mouse xenograft tumor model. Modeling studies suggest that the E2bisMATEs and 2-MeOE2 share a common mode of binding to tubulin, though COMPARE analysis of activity profiles was negative. 21 was cocrystallized with carbonic anhydrase II, and X-ray crystallography revealed unexpected coordination of the 17-O-sulfamate of 21 to the active site zinc and a probable additional lower affinity binding site. 2-Substituted E2bisMATEs are attractive candidates for further development as multitargeted anticancer agents.

Topics: Animals; Antineoplastic Agents; Binding Sites; Breast Neoplasms; Carbonic Anhydrase II; Carcinoma, Lewis Lung; Cell Proliferation; Crystallography, X-Ray; Estradiol; Female; Humans; Mice; Mice, Nude; Models, Molecular; Neovascularization, Pathologic; Steryl-Sulfatase; Structure-Activity Relationship; Sulfonic Acids; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinc