title: Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.
abstract: Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme's structure-function relationships.
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University , 750 East Adams Street, Syracuse, New York 13210, United States.
authors.forename: Debashis
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University , 750 East Adams Street, Syracuse, New York 13210, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lo
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University , 750 East Adams Street, Syracuse, New York 13210, United States.
authors.forename: Chinaza
authors.initials: C
authors.lastname: Egbuta
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D001141:Aromatase