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Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin.

Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA
Cancer Res 64 1802-10 (2004)
Related entries: 1s1p, 1s1r, 1s2c

Cited: 80 times
EuropePMC logo PMID: 14996743

Abstract

It is becoming increasingly well established that nonsteroidal anti-inflammatory drugs (NSAID) protect against tumors of the gastrointestinal tract and that they may also protect against a variety of other tumors. These activities have been widely attributed to the inhibition of cylooxygenases (COX) and, in particular, COX-2. However, several observations have indicated that other targets may be involved. Besides targeting COX, certain NSAID also inhibit enzymes belonging to the aldo-keto reductase (AKR) family, including AKR1C3. We have demonstrated previously that overexpression of AKR1C3 acts to suppress cell differentiation and promote proliferation in myeloid cells. However, this enzyme has a broad tissue distribution and therefore represents a novel candidate for the target of the COX-independent antineoplastic actions of NSAID. Here we report on the X-ray crystal structures of AKR1C3 complexed with the NSAID indomethacin (1.8 A resolution) or flufenamic acid (1.7 A resolution). One molecule of indomethacin is bound in the active site, whereas flufenamic acid binds to both the active site and the beta-hairpin loop, at the opposite end of the central beta-barrel. Two other crystal structures (1.20 and 2.1 A resolution) show acetate bound in the active site occupying the proposed oxyanion hole. The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects.

Reviews - 1s2a mentioned but not cited (4)

  1. AKR1C3 as a target in castrate resistant prostate cancer. Adeniji AO, Chen M, Penning TM. J Steroid Biochem Mol Biol 137 136-149 (2013)
  2. Inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3): overview and structural insights. Byrns MC, Jin Y, Penning TM. J Steroid Biochem Mol Biol 125 95-104 (2011)
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Articles - 1s2a mentioned but not cited (10)

  1. An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Byrns MC, Steckelbroeck S, Penning TM. Biochem Pharmacol 75 484-493 (2008)
  2. Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. Liedtke AJ, Adeniji AO, Chen M, Byrns MC, Jin Y, Christianson DW, Marnett LJ, Penning TM. J Med Chem 56 2429-2446 (2013)
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  4. Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3. Flanagan JU, Yosaatmadja Y, Teague RM, Chai MZ, Turnbull AP, Squire CJ. PLoS One 7 e43965 (2012)
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  8. Bruton's Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3. Morell A, Čermáková L, Novotná E, Laštovičková L, Haddad M, Haddad A, Portillo R, Wsól V. Cancers (Basel) 12 E3731 (2020)
  9. N-Benzoyl anthranilic acid derivatives as selective inhibitors of aldo-keto reductase AKR1C3. Sinreih M, Sosič I, Beranič N, Turk S, Adeniji AO, Penning TM, Rižner TL, Gobec S. Bioorg Med Chem Lett 22 5948-5951 (2012)
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Reviews citing this publication (10)

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  7. Structural basis of the multispecificity demonstrated by 17beta-hydroxysteroid dehydrogenase types 1 and 5. Lin SX, Shi R, Qiu W, Azzi A, Zhu DW, Dabbagh HA, Zhou M. Mol Cell Endocrinol 248 38-46 (2006)
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Articles citing this publication (56)

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  5. Characterization of two novel aldo-keto reductases from Arabidopsis: expression patterns, broad substrate specificity, and an open active-site structure suggest a role in toxicant metabolism following stress. Simpson PJ, Tantitadapitak C, Reed AM, Mather OC, Bunce CM, White SA, Ride JP. J Mol Biol 392 465-480 (2009)
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  9. Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia. Khanim FL, Hayden RE, Birtwistle J, Lodi A, Tiziani S, Davies NJ, Ride JP, Viant MR, Gunther UL, Mountford JC, Schrewe H, Green RM, Murray JA, Drayson MT, Bunce CM. PLoS One 4 e8147 (2009)
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  13. The Recognition of Identical Ligands by Unrelated Proteins. Barelier S, Sterling T, O'Meara MJ, Shoichet BK. ACS Chem Biol 10 2772-2784 (2015)
  14. Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Adeniji AO, Twenter BM, Byrns MC, Jin Y, Winkler JD, Penning TM. Bioorg Med Chem Lett 21 1464-1468 (2011)
  15. Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin. Furlan V, Konc J, Bren U. Molecules 23 E3351 (2018)
  16. Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1). Chen M, Drury JE, Penning TM. Steroids 76 484-490 (2011)
  17. Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism. Jin Y, Duan L, Lee SH, Kloosterboer HJ, Blair IA, Penning TM. J Biol Chem 284 10013-10022 (2009)
  18. Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2. Wu YH, Ko TP, Guo RT, Hu SM, Chuang LM, Wang AH. Structure 16 1714-1723 (2008)
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  23. Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM. J Med Chem 59 7431-7444 (2016)
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  25. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design. Cousido-Siah A, Ruiz FX, Mitschler A, Porté S, de Lera ÁR, Martín MJ, Manzanaro S, de la Fuente JA, Terwesten F, Betz M, Klebe G, Farrés J, Parés X, Podjarny A. Acta Crystallogr D Biol Crystallogr 70 889-903 (2014)
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  28. Crystal structure of anti-configuration of indomethacin and leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complex reveals the structural basis of broad spectrum indomethacin efficacy. Hori T, Ishijima J, Yokomizo T, Ago H, Shimizu T, Miyano M. J Biochem 140 457-466 (2006)
  29. Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate. Khanim F, Davies N, Veliça P, Hayden R, Ride J, Pararasa C, Chong MG, Gunther U, Veerapen N, Winn P, Farmer R, Trivier E, Rigoreau L, Drayson M, Bunce C. Br J Cancer 110 1506-1516 (2014)
  30. Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Hata AN, Lybrand TP, Marnett LJ, Breyer RM. Mol Pharmacol 67 640-647 (2005)
  31. 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. Heinrich DM, Flanagan JU, Jamieson SM, Silva S, Rigoreau LJ, Trivier E, Raynham T, Turnbull AP, Denny WA. Eur J Med Chem 62 738-744 (2013)
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  34. Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics. Gogoi B, Gogoi D, Silla Y, Kakoti BB, Bhau BS. Mol Biosyst 13 406-416 (2017)
  35. Evaluation of solvent accessibility epitopes for different dehydrogenase inhibitors. Ludwig C, Michiels PJ, Lodi A, Ride J, Bunce C, Günther UL. ChemMedChem 3 1371-1376 (2008)
  36. Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3. Endo S, Hu D, Matsunaga T, Otsuji Y, El-Kabbani O, Kandeel M, Ikari A, Hara A, Kitade Y, Toyooka N. Bioorg Med Chem 22 5220-5233 (2014)
  37. 2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3). Gazvoda M, Beranič N, Turk S, Burja B, Kočevar M, Rižner TL, Gobec S, Polanc S. Eur J Med Chem 62 89-97 (2013)
  38. Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells. Doig CL, Battaglia S, Khanim FL, Bunce CM, Campbell MJ. J Steroid Biochem Mol Biol 155 47-55 (2016)
  39. Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo-keto reductase superfamily. Jin Y, Duan L, Chen M, Penning TM, Kloosterboer HJ. J Steroid Biochem Mol Biol 129 139-144 (2012)
  40. Evaluation of A-ring fused pyridine d-modified androstane derivatives for antiproliferative and aldo-keto reductase 1C3 inhibitory activity. Savić MP, Ajduković JJ, Plavša JJ, Bekić SS, Ćelić AS, Klisurić OR, Jakimov DS, Petri ET, Djurendić EA. Medchemcomm 9 969-981 (2018)
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  44. Prophylaxis of posterior capsule opacification through autophagy activation with indomethacin-eluting intraocular lens. Zhang X, Wang J, Xu J, Xu W, Zhang Y, Luo C, Ni S, Han H, Shentu X, Ye J, Ji J, Yao K. Bioact Mater 23 539-550 (2023)
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  52. Crystallization and preliminary X-ray diffraction analysis of mouse prostaglandin F2α synthase, AKR1B3. Takashima Y, Hatanaka S, Mizohata E, Nagata N, Fukunishi Y, Matsumura H, Urade Y, Inoue T. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1630-1632 (2011)
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