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Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.

ABSTRACT: AKR1C3 is a drug target in hormonal and hormonal independent malignancies and acts as a major peripheral 17?-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.

SUBMITTER: Penning TM

PROVIDER: S-EPMC5724044 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.

Penning Trevor M TM

Expert opinion on therapeutic patents 20170919 12

<h4>Introduction</h4>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. Ar ...[more]

PMID: 28895472

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Project description:Aldo-keto reductases (AKRs) are phase I metabolising enzymes that catalyse the reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-dependent reduction of carbonyl groups to yield primary and secondary alcohols on a wide range of substrates, including aliphatic and aromatic aldehydes and ketones, ketoprostaglandins, ketosteroids and xenobiotics. In so doing they functionalise the carbonyl group for conjugation (phase II enzyme reactions). Although functionally diverse, AKRs form a protein superfamily based on their high sequence identity and common protein fold, the (alpha/beta) 8 -barrel structure. Well over 150 AKR enzymes, from diverse organisms, have been annotated so far and given systematic names according to a nomenclature that is based on multiple protein sequence alignment and degree of identity. Annotation of non-vertebrate AKRs at the National Center for Biotechnology Information or Vertebrate Genome Annotation (vega) database does not often include the systematic nomenclature name, so the most comprehensive overview of all annotated AKRs is found on the AKR website (http://www.med.upenn.edu/akr/). This site also hosts links to more detailed and specialised information (eg on crystal structures, gene expression and single nucleotide polymorphisms [SNPs]). The protein-based AKR nomenclature allows unambiguous identification of a given enzyme but does not reflect the wealth of genomic and transcriptomic variation that exists in the various databases. In this context, identification of putative new AKRs and their distinction from pseudogenes are challenging. This review provides a short summary of the characteristic features of AKR biochemistry and structure that have been reviewed in great detail elsewhere, and focuses mainly on nomenclature and database entries of human AKRs that so far have not been subject to systematic annotation. Recent developments in the annotation of SNP and transcript variance in AKRs are also summarised.

Project description:Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts.

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Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.

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Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review.

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