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

References

• Jin Y, Penning TM. Aldo-keto reductases and bioactivation/detoxication. Annu Rev Pharmacol Toxicol. 2007;47:263–292.
   PubMed Web of Science ®Google Scholar
• Penning TM, Drury JE. Human aldo-keto reductases: function, gene regulation and single nucleotide polymorphisms. Arch Biochem Biophys. 2007;464:241–250.
   PubMed Web of Science ®Google Scholar
• Lin H-K, Jez JM, Schlegel BP, et al. Expression and characterization of recombinant type 2 3a-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3a/17b-HSD activity and cellular distribution. Mol Endocrinol. 1997;11:1971–1984.
   PubMed Web of Science ®Google Scholar
• Penning TM, Burczynski ME, Jez JM, et al. Human 3a-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000;351:67–77.
   PubMed Web of Science ®Google Scholar
• Byrns MC, Mindnich R, Duan L, et al. Overexpression of aldo-keto reductase 1C3 (AKR1C3) in LNCaP cells diverts androgen metabolism towards testosterone resulting in resistance to the 5α-reductase inhibitor finasteride. J Steroid Biochem Mol Biol. 2012;130:7–15.
   PubMed Web of Science ®Google Scholar
• Byrns MC, Duan L, Lee S-H, et al. Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its overexpression in breast cancer. J Steroid Biochem Mol Biol. 2010;118:177–187.
   PubMed Web of Science ®Google Scholar
• Penning TM, Steckelbroeck S, Bauman DR, et al. Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol. 2006;248:182–191.
   PubMed Web of Science ®Google Scholar
• Penning TM. Hydroxysteroid dehydrogenases and pre-receptor regulation of steroid hormone action. Hum Reprod Update. 2003;9:193–205.
   PubMed Web of Science ®Google Scholar
• Suzuki-Yamamoto T, Nishizawa M, Fukui M, et al. cDNA cloning, expression and characterization of human prostaglandin F synthase. FEBS Lett. 1999;462:335–340.
   PubMed Web of Science ®Google Scholar
• Matsuura K, Shirasishi H, Hara A, et al. Identification of a principal mRNA species for human 3a-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. J Biochem (Tokyo). 1998;124:940–946.
   PubMed Web of Science ®Google Scholar
• Bauman DR, Rudnick S, Szewczuk L, et al. Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes. Mol Pharmacol. 2005;67:60–68.
   PubMed Web of Science ®Google Scholar
• Desmond JC, Mountford JC, Drayson MT, et al. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Cancer Res. 2003 Jan 15;63(2):505–512.
   PubMed Web of Science ®Google Scholar
• Loriot Y, Fizazi K, Jones RJ, et al. Safety, tolerability and anti-tumor activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. Invest New Drugs. 2014;32:995–1004.
   PubMed Web of Science ®Google Scholar
• Khanim F, Hayden RE, Birtwistle J, et al. Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukemia. PLoS ONE. 2009;4(12):e1847. doi: 10.1371/journal.pone.0008147.
   Google Scholar
• Knudsen K, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009;15:4792–4798.
   PubMed Web of Science ®Google Scholar
• Knudsen K, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010;21:315–324.
   PubMed Web of Science ®Google Scholar
• Attard G, Reid AH, Yap TA, et al. Phase 1 clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;28:4563–4571.
   Web of Science ®Google Scholar
• Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742–37482.
   PubMed Web of Science ®Google Scholar
• Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab. 2012;97:507–516.
   PubMed Web of Science ®Google Scholar
• Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790.
   PubMed Web of Science ®Google Scholar
• Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494–1503.
   PubMed Web of Science ®Google Scholar
• Scher HI, Beer TM, Higano CS, et al. Prostate cancer foundation/department of defense prostate cancer clinical trials consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437–1446.
   PubMed Web of Science ®Google Scholar
• Scher HI, Fizazi K, Saad F, et al. AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–1197.
   PubMed Web of Science ®Google Scholar
• Liu C, Armstrong CM, Lou W, et al. Inhibition of AKR1C3 activation overcomes resistance to abiraterone in advanced prostate cancer. Mol Cancer Ther. 2017;16:35–44.
   PubMed Web of Science ®Google Scholar
• Liu C, Lou W, Zhu Y, et al. Intracrine androgens and AKR1C3 activation confer resistance to Enzalutamide in prostate cancer. Cancer Res. 2015;75:1413–1422.
   PubMed Web of Science ®Google Scholar
• Byrns MC, Steckelbroeck S, Penning TM. An indomethacin analogue N-(4-chlorobenzoyl)melatonin is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3a-HSD, type 5 17b-HSD and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem Pharmacol. 2008;75:484–493.
   PubMed Web of Science ®Google Scholar
• Pelletier G. Expression of steroidogenic enzymes and sex-steroid receptors in human prostate. Best Pract Res Clin Endocrinol Metab. 2008;22:223–228.
   PubMed Web of Science ®Google Scholar
• Hofland J, van Weerden WM, Dits NFJ, et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 2010;70:1256–1264.
   PubMed Web of Science ®Google Scholar
• Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–2825.
   PubMed Web of Science ®Google Scholar
• Mitsiades N, Sung CC, Schultz N, et al. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res. 2012 Dec 1;72(23):6142–6152.
   PubMed Web of Science ®Google Scholar
• Hamid AR, Pfeiffer MJ, Verhaegh GW, et al. Aldo-keto reductase family 1 member C3 (AKR1C3) is a biomarker and therapeutic target for castration-resistant prostate cancer. Mol Med. 2012;18:1449–1455.
   Web of Science ®Google Scholar
• Fankhauser M, Tan Y, Macintyre G, et al. Canoncial androstenedione reduction is the predominat source of signaling androgens in hormone-refractory prostate cancer. Clin Cancer Res. 2014;20:5547–5557.
   PubMed Web of Science ®Google Scholar
• Chang KH, Li R, Papari-Zareei M, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2011;108:13728–13733.
   PubMed Web of Science ®Google Scholar
• Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011;71:1486–1496.
   PubMed Web of Science ®Google Scholar
• Mohler JL, Titus MA, Wilson EM. Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone. Clin Cancer Res. 2011;17:5844–5849.
   PubMed Web of Science ®Google Scholar
• Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab. 2004;15:432–438.
   PubMed Web of Science ®Google Scholar
• Shibuya R, Suzuki T, Miki Y, et al. Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast. Endocr Relat Cancer. 2008 Mar;15(1):113–124.
   PubMed Web of Science ®Google Scholar
• Oduwole OO, Li Y, Isomaa VV, et al. 17beta-hydroxysteroid dehydrogenase type 1 is an independent prognostic marker in breast cancer. Cancer Res. 2004;64:7604–7609.
   PubMed Web of Science ®Google Scholar
• Jansson AK, Gunnarsson C, Cohen M, et al. 17beta-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer. Cancer Res. 2006;66:11471–11477.
   PubMed Web of Science ®Google Scholar
• Steckelbroeck S, Jin Y, Gopishetty S, et al. and Penning TM Human cytosolic 3a-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3b-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action. J Biol Chem. 2003;279:10784–10795.
   PubMed Web of Science ®Google Scholar
• Penning TM, Bauman DR, Jin Y, et al. Identification of the molecular switch that regulates access of 5a-DHT to the androgen receptor. Mol Cell Endocrinol. 2007;265–266:77–82.
   PubMed Web of Science ®Google Scholar
• Bauman DR, Steckelbroeck S, Williams MV, et al. Penning, TM Identification of the major oxidative 3a-hydroxysteroid dehydrogenase in human prostate that converts 5a-andostane-3a,17b-diol to 5a-dihydrotestosterone. A potential therapeutic target for androgen dependent disease. Mol Endocrinol. 2006;20:444–458.
   PubMed Web of Science ®Google Scholar
• Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–174.
   PubMed Web of Science ®Google Scholar
• Sinreih M, Sosič I, Beranič N, et al. N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo-keto reductase AKR1C3. Biorg Med Chem Lett. 2012;22:5948–5951.
   PubMed Web of Science ®Google Scholar
• Gazvoda M, Beranič N, Turk S, et al. 2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3). Eur J Med Chem. 2013;62:89–97.
   PubMed Web of Science ®Google Scholar
• Skarydova L, Hofman J, Chlebek J, et al. Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors. J Steroid Biochem Mol Biol. 2014;143:2508.
   Web of Science ®Google Scholar
• Skarydová L, Zivná L, Xiong G, et al. AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chem Biol Inter. 2009;178:138–144.
   PubMed Web of Science ®Google Scholar
• Heinrich DM, Flanagan JU, Jamieson SM, et al. Synthesis and structure-activity relationships for 1-(4-(piperidin-1-ylsulfonyl)phenyl)pyrrolidin-2-ones as novel non-carboxylate inhibitors of the aldo-keto reductase enzyme AKR1C3. Eur J Med Chem. 2013;62:738–744.
   PubMed Web of Science ®Google Scholar
• Kikuchi A, Furutani T, Azami H, et al. In vitro and in vivo characterization of ASP9521: a novel selective, orally bioavailable inhibitor of 17b-hydroxysteroid dehydrogenase type 5 (17b-HSD5; AKR1C3). Invest New, Drugs. 2014;32:860–870.
   PubMed Web of Science ®Google Scholar
• Adeniji AO, Twenter BM, Byrns MC, et al. Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Bioorg Med Chem Lett. 2011;21:1464–1468.
   PubMed Web of Science ®Google Scholar
• Adeniji AO, Twenter BM, Byrns MC, et al. Development of potent and selective inhibitors of aldo-keto reductase 1C3 (type 5 17β-hydroxysteroid dehydrogenase) based on N-phenyl-aminobenzoates and their structure-activity relationships. J Med Chem. 2012;55:2311–2323.
   PubMed Web of Science ®Google Scholar
• Adeniji A, Uddin MJ, Zang T, et al. Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic acid as a potent and selective Aldo-keto reductase 1C3 inhibitor. J Med Chem. 2016 Aug 25;59(16):7431–7444.
   PubMed Web of Science ®Google Scholar
• Liedtke AJ, Kim K, Stec DF, et al. Straightforward protocol for the efficient synthesis of varied N1-acylated (aza)indole 2-/3-alkanoic acids and esters: optimization and scaleup. Tetrahedron. 2012;I68:10049–10058.
   Web of Science ®Google Scholar
• Liedtke AJ, Adeniji AO, Chen M, et al. Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (type 5 17b-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem. 2013 Mar 28;56(6):2429–2446.
   PubMed Web of Science ®Google Scholar
• Yamamoto H. 1-Acyl-indoles II. A new synthesis of 1-(ionchlorobenzoyl)-5-methoxy-3-indolylacetic acid and its polymorphism. Chem Pharm Bull. 1968;16:17–19.
   PubMed Web of Science ®Google Scholar
• Conn RSE, Douglas AW, Karday S, et al. An unusual Fischer indole synthesis with 4-ketoacids: an indole incorprorating the terminal hydrazine nitrogen. J Org Chem. 1990;55:2908–2913.
   Web of Science ®Google Scholar
• Allen GR Jr. Selectivity in the Fischer indolization of phenylhydrazones derived from 3-ketocyclohexanecrboxylic acid. J Heterocycl Chem. 1970;7:239–241.
   Web of Science ®Google Scholar
• Yepuru M, Wu Z, Kyulkarni A, et al. Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clin Cancer Res. 2013;19:5613–5625.
   PubMed Web of Science ®Google Scholar
• Chen M, Adeniji AO, Twenter BM, et al. Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. Bioorg Med Chem Lett. 2012;22:3492–3497.
   PubMed Web of Science ®Google Scholar
• Zang T, Verma K, Chen M, et al. Screening baccharin analogs as selective inhibitors against type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Chem Biol Interact. 2015 Jun 05;234:339–348.
   PubMed Web of Science ®Google Scholar
• Endo S, Matsunaga T, Kanamori A, et al. Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J Nat Prod. 2012;27:716–721.
   Web of Science ®Google Scholar
• Byrns MC, Jin Y, Penning TM. Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): overview and structural insights. J Steroid Biochem Mol Biol. 2011;125:95–104.
   PubMed Web of Science ®Google Scholar
• Andersson S, Geissler WM, Patel S, et al. The molecular biology of androgenic 17b-hydroxysteroid dehydrogenases. J Steroid Biochem Mol Biol. 1995;53:37–39.
   PubMed Web of Science ®Google Scholar
• Taplin ME, Montgomery B, Logothetis CJ, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014;32:3705–3715.
   PubMed Web of Science ®Google Scholar
• Tamae D, Mostaghel E, Montgomery B, et al. The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Inter. 2015;234:332–338.
   PubMed Web of Science ®Google Scholar
• Chang K-H, Li R, Kuri B, et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013;154:1074–1084.
   PubMed Web of Science ®Google Scholar
• Pfeiffer MJ, Smit FP, Sedelaar JP, et al. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer. Mol Med. 2011;17(7–8):657–664.
   PubMed Web of Science ®Google Scholar
• Thompson IM, Chi C, Ankerst DP, et al. Prediction of prostate cancer for patients receiving finasteride: results from the prostate cancer prevention trial. J Clin Oncol. 2007;25:3076–3081.
   PubMed Web of Science ®Google Scholar
• Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–406.
   PubMed Web of Science ®Google Scholar
• Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–1398.
   PubMed Web of Science ®Google Scholar
• Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999;59:2511–2515.
   PubMed Web of Science ®Google Scholar
• Yu Z, Chen S, Sowalsky AG, et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 2014;20:1590–1600.
   PubMed Web of Science ®Google Scholar
• Sprenger CCT, Plymate SR. The link between androgen receptor splice variants and castration-resistant prostate cancer. Hormones & Cancer. 2014;5:207–2014.
   PubMed Web of Science ®Google Scholar
• Cao B, Qi Y, Zhang G, et al. Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget. 2014;5:1646–1656.
   PubMed Web of Science ®Google Scholar