title: Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health.
abstract: 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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath , Claverton Down, Bath BA2 7AY, United Kingdom.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D055808:Drug Discovery; D004715:Endometriosis / Q000188:drug therapy; D004970:Estrone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D013451:Sulfonic Acids; D050257:Tubulin Modulators; C088768:estrone-3-O-sulfamate; D004970:Estrone; C520511:irosustat; C005741:sulfamic acid; D043266:Steryl-Sulfatase