期刊
EXPERT OPINION ON THERAPEUTIC PATENTS
卷 27, 期 12, 页码 1329-1340出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/13543776.2017.1379503
关键词
Acute myeloid leukemia; aldo-keto reductase; androgen receptor; baccharin; co-activator; estrenes; 17 beta-hydroxysteroid dehydrogenase; indomethacin; non-steroidal anti-inflammatory drugs; prostate cancer
资金
- National Institutes of Health [P30-ES013508, P01-CA163227]
Introduction: AKR1C3 is a drug target in hormonal and hormonal independent malignancies and acts as a major peripheral 17 beta-hydroxysteroid dehydrogenase to yield the potent androgens testosterone and dihydrotestosterone, and as a prostaglandin (PG) F synthase to produce proliferative ligands for the PG FP receptor. AKR1C3 inhibitors may have distinct advantages over existing therapeutics for the treatment of castration resistant prostate cancer, breast cancer and acute myeloid leukemia. Area covered: This article reviews the patent literature on AKR1C3 inhibitors using SciFinder which identified inhibitors in the following chemical classes: N-phenylsulfonyl-indoles, N-(benzimidazoylylcarbonyl)-N-( indoylylcarbonyl)- and N-(pyridinepyrrolyl)-piperidines, N-benzimidazoles and N-benzindoles, repurposed nonsteroidal antiinflammatory drugs (indole acetic acids, N-phenylanthranilates and aryl propionic acids), isoquinolines, and nitrogen and sulfur substituted estrenes. The article evaluates inhibitor AKR potency, specificity, efficacy in cell-based and xenograft models and clinical utility. The advantage of bifunctional compounds that either competitively inhibit AKR1C3 and block its androgen receptor (AR) coactivator function or act as AKR1C3 inhibitors and direct acting AR antagonists are discussed. Expert opinion: A large number of potent and selective inhibitors of AKR1C3 have been described however, preclinical optimization, is required before their benefit in human disease can be assessed.
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