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ABSTRACT
Introduction: AKR1C3 is a drug target in hormonal and hormonal independent malignancies and acts as a major peripheral 17β-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.
Article highlights
AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F2α synthase) is a drug target for hormonal and hormonal independent malignancies
Nonsteroidal inhibitors, repurposed NSAIDs and steroid based inhibitors have been claimed in multiple patent applications
Extensive steroidal-based inhibitors based on C3 and C17 substituted estrenes have been developed
AKR1C3 inhibitors have progressed to clinical trials for castration resistant prostate cancer and acute myeloid leukemia with mixed success
The majority of inhibitors require optimization for testing in animals and humans
This box summarizes key points contained in the article.
Acknowledgements
This author apologizes for the inability to describe many important studies due to space limitations.
Declaration of interest
Dr. Penning is founder of Penzymes, LLC, and is a consultant for Sage Pharmaceutics, Syrrix and Tokai Pharmaceuticals and has a Sponsored Research Agreement with Forendo.
