irosustat 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

A novel approach for the dual inhibition of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β HSD1) by a single drug was explored, starting from in-house 17β HSD1 inhibitors via masking their phenolic OH group with a sulfamate ester. The sulfamates were intentionally designed as drugs for the inhibition of STS and, at the same time, prodrugs for 17β-HSD1 inhibition ("drug-prodrug approach"). The most promising sulfamates

Topics: 17-Hydroxysteroid Dehydrogenases; Endometriosis; Enzyme Inhibitors; Female; Humans; Phenols; Prodrugs; Steryl-Sulfatase; Structure-Activity Relationship

STS and 17β-HSD1 are attractive targets for the treatment of estrogen-dependent diseases like endometriosis and breast cancer. The simultaneous inhibition of both enzymes appears more promising than blockage of either protein alone. We describe a designed multiple ligand approach resulting in highly potent dual inhibitors. The most interesting compound 9 showed nanomolar IC

Topics: 17-Hydroxysteroid Dehydrogenases; Breast Neoplasms; Cell Proliferation; Endometriosis; Enzyme Inhibitors; Female; Humans; Ligands; Steryl-Sulfatase

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

Endometriosis is a common and debilitating condition of women in their reproductive age that is associated with pain and infertility. Current medical treatments are only partially effective and associated with wide-ranging side effects. New understanding of local estrogen production by endometriotic tissue and the availability of powerful suppressing drugs may herald a new era in the treatment of this condition.

Topics: Adult; Coumarins; Disease Progression; Endometriosis; Enzyme Inhibitors; Estrogens; Female; Humans; Ovary; Steryl-Sulfatase; Sulfonamides; Sulfonic Acids; Treatment Outcome

Local biosynthesis of estrogens is thought to be important for the maintenance and growth of endometriotic implants. In addition to the formation of estrogen via the aromatase pathway, steroid sulphatase (STS), which is responsible for the hydrolysis of estrogen sulphates, may be an important source of estrogens in endometriosis.. Eutopic and ectopic endometrial samples from 14 women with minimal or mild (MM) endometriosis and from 13 women with moderate to severe (MS) endometriosis were analysed for aromatase and STS activities.. Aromatase and STS activity were detected in all samples. STS enzyme activity in both eutopic and ectopic endometrium was considerably higher and less variable than aromatase activity. Moreover, STS, but not aromatase, activity in endometriotic implants correlated with the severity of the disease (mean +/- SEM: 203 +/- 38 nmol/4 h/g wet weight tissue in MM disease versus 423 +/- 44 nmol/4 h/g wet weight tissue in MS endometriosis, P < 0.001). The STS inhibitor 667 COUMATE almost completely blocked STS activity (>99%) in both eutopic and ectopic tissues.. The high levels of STS activity detected in ectopic endometrium and the correlation with severity of disease suggest that STS inhibitors could be useful for the treatment of endometriosis.

Topics: Adult; Aromatase; Coumarins; Endometriosis; Endometrium; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Middle Aged; Severity of Illness Index; Steryl-Sulfatase; Sulfonamides; Sulfonic Acids