Aldo-Keto Reductase

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Trevor M. Penning - One of the best experts on this subject based on the ideXlab platform.

  • The Aldo-Keto Reductase Superfamily
    Comprehensive Toxicology, 2020
    Co-Authors: Trevor M. Penning
    Abstract:

    Aldo-Keto Reductases (AKRs) are a gene superfamily whose members catalyze the nicotinamide adenine dinucleotide (phosphate) reduced dependent interconversion of aldehydes and ketones with primary and secondary alcohols. AKRs by functionalizing carbonyl groups for subsequent conjugation reactions are considered Phase I enzymes. There are 15 human AKR isoforms which are pluripotent. Endogenous substrates include sugar aldehydes, lipid aldehydes, prostaglandins, and steroid hormones. Xenobiotic substrates include carbonyl containing drugs and carcinogen metabolites (polycyclic aromatic trans -dihydrodiols, nicotine derived nitrosamino-ketones, and aflatoxin dialdehyde); and they have been implicated in cancer chemotherapeutic drug resistance. Human isoforms are regulated by primordial signals (osmotic, electrophilic, and oxidative stress) so that a counterresponse to the stressor may ensue. Many contain an Anti-oxidant Response Element in their gene promoters suggesting that cancer chemopreventive strategies that target this element could also affect endogenous and exogenous substrate utilization.

  • Aldo-Keto Reductase 1C3-Assessment as a new target for the treatment of endometriosis.
    Pharmacological Research, 2019
    Co-Authors: Tea Lanišnik Rižner, Trevor M. Penning
    Abstract:

    Abstract Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed phase I trial and a recent phase II trial that investigated the steroidal Aldo-Keto Reductase 1C3 (AKR1C3) inhibitor BAY1128688 in endometriosis patients prompted this critical assessment on the role of AKR1C3 in endometriosis. This review includes an introduction to endometriosis with emphasis on the roles of prostaglandins and progesterone in its pathophysiology. This is followed by an overview of the major enzymatic activities and physiological functions of AKR1C3 and of the data published to date on the expression of AKR1C3 in endometriosis at the mRNA and protein levels. The review concludes with the rationale for using AKR1C3 inhibitors, a discussion of the effects of AKR1C3 inhibition on the pathophysiology of endometriosis and a brief overview of other drugs under clinical investigation for this indication.

  • potent and highly selective aldo keto Reductase 1c3 akr1c3 inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and t cell acute lymphoblastic leukemia
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Kshitij Verma, Tianzhu Zang, Trevor M. Penning, Paul C Trippier
    Abstract:

    Aldo–keto Reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines: first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactivate 5α-dihydrotestosterone, and their inhibition would be undesirable. We report herein the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biological evaluation of our isoform-selective inhibitors revealed a high degree of synergistic drug action in combination with the clinical leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compounds exhibi...

  • aldo keto Reductase family 1 member c3 akr1c3 is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma
    International Journal of Clinical and Experimental Pathology, 2012
    Co-Authors: Valerie L Miller, Paari Murugan, Lacy S Brame, Trevor M. Penning, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.

  • original article aldo keto Reductase family 1 member c3 akr1c3 is expressed in adenocarcinoma and squamous cell car cinoma but not small cell carcinoma
    2012
    Co-Authors: Valerie L Miller, Paari Murugan, Lacy S Brame, Trevor M. Penning, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androster- one. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids includ- ing estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin Reductase activ- ity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endo- metrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demon- strated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junc- tion. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunore- activity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma patho- genesis require further studies.

Kar Ming Fung - One of the best experts on this subject based on the ideXlab platform.

  • Original Article Expression of Aldo-Keto Reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung
    2020
    Co-Authors: Theodore S Chang, Lacy S Brame, Kyle A Rogers, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reduc - ing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and ad- enocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tis- sue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3's role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

  • expression of aldo keto Reductase family 1 member c3 akr1c3 in neuroendocrine tumors adenocarcinomas of pancreas gastrointestinal tract and lung
    International Journal of Clinical and Experimental Pathology, 2013
    Co-Authors: Theodore S Chang, Lacy S Brame, Kyle A Rogers, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

  • Expression of Aldo-Keto Reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung.
    International Journal of Clinical and Experimental Pathology, 2013
    Co-Authors: Theodore S Chang, Lacy S Brame, Kyle A Rogers, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

  • aldo keto Reductase family 1 member c3 akr1c3 is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma
    International Journal of Clinical and Experimental Pathology, 2012
    Co-Authors: Valerie L Miller, Paari Murugan, Lacy S Brame, Trevor M. Penning, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.

  • original article aldo keto Reductase family 1 member c3 akr1c3 is expressed in adenocarcinoma and squamous cell car cinoma but not small cell carcinoma
    2012
    Co-Authors: Valerie L Miller, Paari Murugan, Lacy S Brame, Trevor M. Penning, Qing Yang, Kar Ming Fung
    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17β-diol (3α-diol) and oxidizing 3α-diol to androster- one. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17β-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids includ- ing estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin Reductase activ- ity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endo- metrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demon- strated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junc- tion. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunore- activity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma patho- genesis require further studies.

Yoshiteru Kamiyma - One of the best experts on this subject based on the ideXlab platform.

Stephan Steckelbroeck - One of the best experts on this subject based on the ideXlab platform.

  • an indomethacin analogue n 4 chlorobenzoyl melatonin is a selective inhibitor of aldo keto Reductase 1c3 type 2 3α hsd type 5 17β hsd and prostaglandin f synthase a potential target for the treatment of hormone dependent and hormone independent malig
    Biochemical Pharmacology, 2008
    Co-Authors: Michael C Byrns, Stephan Steckelbroeck, Trevor M. Penning
    Abstract:

    Abstract Aldo-Keto Reductase (AKR) 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase) regulates ligand access to steroid hormone and prostaglandin receptors and may stimulate proliferation of prostate and breast cancer cells. NSAIDs are known inhibitors of AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C family members would provide an important tool to examine the role of AKR1C3 in proliferative signaling. We tested NSAIDs and NSAID analogues for inhibition of the reduction of 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoforms AKR1C1 and AKR1C2. Two of the compounds initially screened, indomethacin and its methyl ester, were specific for AKR1C3 versus the other AKR1C isoforms. Based on these results and the crystal structure of AKR1C3, we predicted that N -(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction of PQ by AKR1C3, but did not significantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction of Δ 4 -androstene-3,17-dione but did not significantly inhibit the reduction of steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern of inhibition of AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Δ 4 -androstene-3,17-dione, indicating that two different inhibitory complexes form during the ordered bi bi reactions. The identification of CBM as a specific inhibitor of AKR1C3 will aid the investigation of its roles in steroid hormone and prostaglandin signaling and the resultant effects on cancer development.

  • characterization of a monoclonal antibody for human aldo keto Reductase akr1c3 type 2 3α hydroxysteroid dehydrogenase type 5 17β hydroxysteroid dehydrogenase immunohistochemical detection in breast and prostate
    Steroids, 2004
    Co-Authors: Stephan Steckelbroeck, Kar Ming Fung, Amy N Jones, Trevor M. Penning
    Abstract:

    Human Aldo-Keto Reductase AKR1C3 (type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase) catalyzes the reduction of Δ4-androstene-3,17-dione to yield testosterone, the reduction of 5α-dihydrotestosterone to yield 3α- and 3β-androstanediol, and the reduction of estrone to yield 17β-estradiol. Relatively, high mRNA expression of AKR1C3 was found in human prostate and mammary gland where it is implicated in regulating ligand access to the androgen and estrogen receptor, respectively. AKR1C3 shares high sequence identity >86% with related plastic human 20α-hydroxysteroid dehydrogenases (AKR1C1), type 3 3α-hydroxysteroid dehydrogenase (AKR1C2) and type 1 3α-hydroxysteroid dehydrogenase (AKR1C4), and reagents are urgently needed to discriminate between these enzymes at the mRNA, protein and functional level. We describe the characterization of a high-titer isoform specific monoclonal antibody (Ab) for AKR1C3. It does not cross react with human AKR1C1, AKR1C2 or AKR1C4, human aldehyde Reductase AKR1A1 or rat 3α-hydroxysteroid dehydrogenase (AKR1C9) on immunoblot analysis. The monoclonal Ab can be used to detect AKR1C3 expression by immunohistochemistry in sections of paraffin-embedded mammary gland and prostate. In the breast enzyme staining was detected in ductal carcinoma in situ where the cancerous cells were strongly immunoreactive. In normal prostate immunoreactivity was limited to stromal cells with only faint staining in the epithelial cells. In adenocarcinoma of the prostate elevated staining was observed in the endothelial cells and carcinoma cells. The reagent thus has utility to access the localized expression of AKR1C3 in hormonal dependent malignancies of the breast and prostate.

Agnese Chiara Pippione - One of the best experts on this subject based on the ideXlab platform.

  • Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.
    ACS Medicinal Chemistry Letters, 2019
    Co-Authors: Marco L. Lolli, Agnese Chiara Pippione, Davide Bonanni, Irene Maria Carnovale, Elisabetta Marini, Daniele Zonari, W.y. Wahlgren, Margherita Gallicchio, Valentina Boscaro, Parveen Goyal
    Abstract:

    Aldo-Keto Reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known...

  • potent and selective aldo keto Reductase 1c3 akr1c3 inhibitors based on the benzoisoxazole moiety application of a bioisosteric scaffold hopping approach to flufenamic acid
    European Journal of Medicinal Chemistry, 2018
    Co-Authors: Agnese Chiara Pippione, Davide Bonanni, Irene Maria Carnovale, Elisabetta Marini, Daniele Zonari, Klaus Pors, Marcella Sini, Salvatore Adinolfi, Parveen Goyal, Claudio Festuccia
    Abstract:

    Abstract The Aldo-Keto Reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.

  • hydroxytriazole derivatives as potent and selective aldo keto Reductase 1c3 akr1c3 inhibitors discovered by bioisosteric scaffold hopping approach
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Agnese Chiara Pippione, Davide Bonanni, Irene Maria Carnovale, Elisabetta Marini, Annalisa Costale, Daniele Zonari, Klaus Pors, Clara Cena, Alessandro Giraudo, Maria Sadiq
    Abstract:

    The Aldo-Keto Reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.