Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors

PLoS ONE

Volumn 9, Issue 3, 2014, Pages

  Schmitt, Christian ^a   Kail, Dagmar ^b   Mariano, Marica ^a   Empting, Martin ^c   Weber, Nadja ^a   Paul, Tamara ^a   Hartmann, Rolf W ^a,c   Engel, Matthias ^a  

^a SAARLAND UNIVERSITY   (Germany)

^b PharmBioTec GmbH   (Germany)

^c SAARLAND UNIVERSITY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1 [5 [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]PYRIDIN 3 YL]ETHAN 1 ONE; 2 (TRIMETHYLSILYL) 1,3 THIAZOLE; 2,4 BISHETEROCYCLIC SUBSTITUTED THIOPHENE; 3 (4 BROMOTHIOPHEN 2 YL)PYRIDINE; 3 FLUORO 5 [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]PYRIDINE; 3 METHOXY 5 [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]PYRIDINE; 3 METHYL 5 [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]PYRIDINE; 3 [4 (1 METHYL 1H PYRAZOL 4 YL)THIOPHEN 2 YL]PYRIDINE; 3 [4 (1,3 THIAZOL 5 YL)THIOPHEN 2 YL]PYRIDINE; 3 [5 (1,3 OXAZOL 5 YL)THIOPHEN 3 YL]PYRIDINE; 3 [5 (1,3 THIAZOL 5 YL)THIOPHEN 3 YL]PYRIDINE; 5 (4 BROMOTHIOPHEN 2 YL) 1,3 OXAZOLE; 5 (4 BROMOTHIOPHEN 2 YL) 1,3 THIAZOLE; 5 (4 BROMOTHIOPHEN 2 YL)PYRIMIDINE; 5 (TETRAMETHYL 1,3,2 DIOXABOROLAN 2 YL) 1,3 THIAZOLE; 5 [4 (PYRIDIN 3 YL)THIOPHEN 2 YL]PYRIMIDINE; 5 [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]PYRIDINE 3 CARBOXAMIDE; ENZYME INHIBITOR; THIOPHENE DERIVATIVE; UNCLASSIFIED DRUG; [5 (PYRIDIN 3 YL)THIOPHEN 3 YL]BORONIC ACID; CASPASE 3; CASPASE 7; CLK DUAL-SPECIFICITY KINASES; DYRK KINASE; HYBRID PROTEIN; MOLECULAR LIBRARY; PROTEIN KINASE INHIBITOR; PROTEIN SERINE THREONINE KINASE; PROTEIN TYROSINE KINASE; REACTIVE OXYGEN METABOLITE;

ARTICLE; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; PHYSICAL CHEMISTRY; PROTEIN TARGETING; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG EFFECTS; DRUG SCREENING; GENE EXPRESSION REGULATION; HAMSTER; HUMAN; IC50; METABOLISM; MOLECULAR LIBRARY; PROCEDURES; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TUMOR CELL LINE;

ANIMALS; CASPASE 3; CASPASE 7; CELL LINE, TUMOR; CRICETINAE; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; DRUG SCREENING ASSAYS, ANTITUMOR; GENE EXPRESSION REGULATION; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PROTEIN-TYROSINE KINASES; REACTIVE OXYGEN SPECIES; RECOMBINANT FUSION PROTEINS; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 84899847151     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0087851     Document Type: Article

References (100)

1. Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, et al. (1998) Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem 273: 25893-25902. Available: http://www.ncbi.nlm.nih.gov/pubmed/ 9748265.
2. Becker W, Joost HG (1999) Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog Nucleic Acid Res Mol Biol 62: 1-17. Available: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=9932450.
3. Woods YL, Cohen P, Becker W, Jakes R, Goedert M, et al. (2001) The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Be at Ser539 and the microtubule-associated protein tau at Thr212 for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J 355: 609-615. (Pubitemid 32434076)
4. Ryoo S-RR, Jeong HK, Radnaabazar C, Yoo J-JJ, Cho H-JJ, et al. (2007) DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease. J Biol Chem 282: 34850-34857. Available: http://www.ncbi.nlm.nih.gov/pubmed/17906291. Accessed: 17 Jul 2012.
5. Liu F, Liang Z, Wegiel J, Hwang Y-WW, Iqbal K, et al. (2008) Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J 22: 3224-3233. Available: http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=18509201. Accessed: 16 Jul 2012.
6. Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30: 1757-1768. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=20123978.
7. Johnson G V, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117: 5721-5729. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=15537830.
8. Steinhilb ML, Dias-Santagata D, Fulga TA, Felch DL, Feany MB (2007) Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18: 5060-5068. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=17928404.
9. Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, et al. (2007) The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet 16: 15-23. Available: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=17135279.
10. Wegiel JJ, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, et al. (2008) The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome. Acta Neuropathol 116: 391-407. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2656568&tool= pmcentrez&rendertype=abstract. Accessed: 16 Jul 2012.
11. Shi J, Zhang T, Zhou C, Chohan MO, Gu X, et al. (2008) Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. J Biol Chem 283: 28660-28669. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2568927&tool= pmcentrez&rendertype=abstract. Accessed: 17 Jul 2012.
12. De Graaf K, Czajkowska H, Rottmann S, Packman LC, Lilischkis R, et al. (2006) The protein kinase DYRK1A phosphorylates the splicing factor SF3b1/SAP155 at Thr434, a novel in vivo phosphorylation site. BMC Biochem 7: 7. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1420302&tool= pmcentrez&rendertype=abstract. Accessed: 22 May 2013.
13. Álvarez M, Estivill X, de La Luna S (2003) DYRK1A accumulates in splicing speckles through a novel targeting signal and induces speckle disassembly. J Cell Sci 116: 3099-3107. doi:10.1242/jcs.00618 (Pubitemid 37038959)
14. Yin X, Jin N, Gu J, Shi J, Zhou J, et al. (2012) Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion. J Biol Chem 287: 30497-30506. Available: http://www.ncbi.nlm.nih.gov/pubmed/22767602. Accessed: 5 Jul 2013.
15. Wegiel J, Kaczmarski W, Barua M, Kuchna I, Nowicki K, et al. (2011) Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome. J Neuropathol Exp Neurol 70: 36-50. Available: http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=3083064&tool=pmcentrez&rendertype=abstract.
16. Hartmann a M, Rujescu D, Giannakouros T, Nikolakaki E, Goedert M, et al. (2001) Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors. Mol Cell Neurosci 18: 80-90. Available: http://www.ncbi.nlm.nih.gov/pubmed/11461155. Accessed: 5 Jul 2013.
17. Giraud F, Alves G, Debiton E, Nauton L, Théry V, et al. (2011) Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of meridianin derivatives. J Med Chem 54: 4474-4489. Available: http://www.ncbi.nlm.nih.gov/pubmed/21623630.
18. Rosenthal AS, Tanega C, Shen M, Mott BT, Bougie JM, et al. (2011) Potent and selective small molecule inhibitors of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine-phosphorylation-regulated kinases (Dyrk). Bioorg Med Chem Lett 21: 3152-3158. Available: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3085634&tool=pmcentrez&rendertype= abstract. Accessed: 17 Jul 2012.
19. Mott BT, Tanega C, Shen M, Maloney DJ, Shinn P, et al. (2009) Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk). Bioorg Med Chem Lett 19: 6700-6705. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2807730&tool= pmcentrez&rendertype=abstract. Accessed: 14 Jun 2013.
20. Fedorov O, Huber K, Eisenreich A, Filippakopoulos P, King O, et al. (2011) Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem Biol 18: 67-76. Available: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3145970&tool=pmcentrez&rendertype= abstract. Accessed: 20 Jun 2013.
21. Debdab M, Carreaux F, Renault S, Soundararajan M, Fedorov O, et al. (2011) Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem 54: 4172-4186. Available: http://www.ncbi.nlm.nih.gov/pubmed/21615147.
22. Mercer SE, Friedman E (2006) Mirk/Dyrk1B: a multifunctional dual-specificity kinase involved in growth arrest, differentiation, and cell survival. Cell Biochem Biophys 45: 303-315. Available: http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list- uids=16845176.
23. Friedman E (2007) Mirk/Dyrk1B in cancer. J Cell Biochem 102: 274-279. Available: http://www.ncbi.nlm.nih.gov/pubmed/17583556. Accessed: 17 Jul 2012.
24. Mercer SE, Ewton DZ, Deng X, Lim S, Mazur TR, et al. (2005) Mirk/Dyrk1B mediates survival during the differentiation of C2C12 myoblasts. J Biol Chem 280: 25788-25801. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=15851482.
25. Deng X, Ewton DZ, Pawlikowski B, Maimone M, Friedman E (2003) Mirk/dyrk1B is a Rho-induced kinase active in skeletal muscle differentiation. J Biol Chem 278: 41347-41354. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=12902328.
26. Jin K, Park S, Ewton DZ, Friedman E (2007) The survival kinase Mirk/Dyrk1B is a downstream effector of oncogenic K-ras in pancreatic cancer. Cancer Res 67: 7247-7255. Available: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=17671193.
27. Deng X, Mercer SE, Shah S, Ewton DZ, Friedman E (2004) The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G(0) by Mirk/dyrk1B kinase. J Biol Chem 279: 22498-22504. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 15010468.
28. Vervoorts J, Luscher B (2008) Post-translational regulation of the tumor suppressor p27(KIP1). CellMol Life Sci 65: 3255-3264. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=18636226.
29. Zou Y, Ewton DZ, Deng X, Mercer SE, Friedman E (2004) Mirk/dyrk1B kinase destabilizes cyclin D1 by phosphorylation at threonine 288. J Biol Chem 279: 27790-27798. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=15075324.
30. Yabut O, Domogauer J, D'Arcangelo G (2010) Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J Neurosci 30: 4004-4014. Available: http://www.ncbi.nlm.nih. gov/pubmed/20237271. Accessed: 17 Jul 2012.
31. Becker W (2012) Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control. Cell Cycle 11: 3389-3394. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 3466549&tool=pmcentrez&rendertype=abstract. Accessed: 9 Nov 2012.
32. Ewton DZ, Hu J, Vilenchik M, Deng X, Luk KC, et al. (2011) Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells. Mol Cancer Ther 10: 2104-2114. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=21878655.
33. Hu J, Nakhla H, Friedman E (2011) Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. Int J Cancer 129: 307-318. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=20857490.
34. Skurat A V, Dietrich AD (2004) Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem 279: 2490-2498. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=14593110.
35. Mazmanian G, Kovshilovsky M, Yen D, Mohanty A, Mohanty S, et al. (2010) The zebrafish dyrk1b gene is important for endoderm formation. Genesis 48: 20-30. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=20014342.
36. Miyata Y, Nishida E (2011) DYRK1A binds to an evolutionarily conserved WD40-repeat protein WDR68 and induces its nuclear translocation. Biochim Biophys Acta 1813: 1728-1739. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi? cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=21777625.
37. Chang HS, Lin CH, Yang CH, Yen MS, Lai CR, et al. (2007) Increased expression of Dyrk1a in HPV16 immortalized keratinocytes enable evasion of apoptosis. Int J Cancer 120: 2377-2385. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 17294446.
38. Pozo N, Zahonero C, Fernández P, Liñares JM, Ayuso A, et al. (2013) Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. J Clin Invest 123: 2475-2487. doi:10.1172/JCI63623.The.
39. Miller CT, Aggarwal S, Lin TK, Dagenais SL, Contreras JI, et al. (2003) Amplification and overexpression of the dual-specificity tyrosine-(Y)- phosphorylation regulated kinase 2 (DYRK2) gene in esophageal and lung adenocarcinomas. Cancer Res 63: 4136-4143. Available: http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list- uids=12874018.
40. Koon N, Schneider-Stock R, Sarlomo-Rikala M, Lasota J, Smolkin M, et al. (2004) Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut 53: 235-240. Available: http://www.ncbi.nlm.nih.gov/entrez/query. fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids=14724156.
41. Taira N, Mimoto R, Kurata M, Yamaguchi T, Kitagawa M, et al. (2012) DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells. J Clin Invest 122: 859-872. Available: http://www.ncbi.nlm. nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt= Citation&list-uids=22307329.
42. Yamashita S, Chujo M, Moroga T, Anami K, Tokuishi K, et al. (2009) DYRK2 expression may be a predictive marker for chemotherapy in non-small cell lung cancer. Anticancer Res 29: 2753-2757. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 19596956.
43. Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K (2007) DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell 25: 725-738. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=17349958.
44. Jung H-Y, Wang X, Jun S, Park J-I (2013) Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation. J Biol Chem 288: 7252-7262. Available: http://www.ncbi.nlm.nih.gov/pubmed/23362280. Accessed: 27 Feb 2013.
45. Geiger JN, Knudsen GT, Panek L, Pandit AK, Yoder MD, et al. (2001) mDYRK3 kinase is expressed selectively in late erythroid progenitor cells and attenuates colony-forming unit-erythroid development. Blood 97: 901-910. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=11159515.
46. Lord KA, Creasy CL, King AG, King C, Burns BM, et al. (2000) REDK, a novel human regulatory erythroid kinase. Blood 95: 2838-2846. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=10779429.
47. Rush J, Moritz A, Lee KA, Guo A, Goss VL, et al. (2005) Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol 23: 94-101. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=15592455.
48. Slepak TI, Salay LD, Lemmon VP, Bixby JL (2012) Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskelet 69: 514-527. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 22359282.
49. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, et al. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408: 297-315. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=17850214.
50. Kim H, Sablin SO, Ramsay RR (1997) Inhibition of monoamine oxidase A by beta-carboline derivatives. Arch Biochem Biophys 337: 137-142. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=8990278.
51. Miralles A, Esteban S, Sastre-Coll A, Moranta D, Asensio VJ, et al. (2005) High-affinity binding of beta-carbolines to imidazoline I2B receptors and MAO-A in rat tissues: norharman blocks the effect of morphine withdrawal on DOPA/noradrenaline synthesis in the brain. Eur J Pharmacol 518: 234-242. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=16061219.
52. Boeira JM, da Silva J, Erdtmann B, Henriques JA (2001) Genotoxic effects of the alkaloids harman and harmine assessed by comet assay and chromosome aberration test in mammalian cells in vitro. Pharmacol Toxicol 89: 287-294. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=11903953.
53. Boeira JM, Viana AF, Picada JN, Henriques JA (2002) Genotoxic and recombinogenic activities of the two beta-carboline alkaloids harman and harmine in Saccharomyces cerevisiae. Mutat Res 500: 39-48. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=11890933.
54. Jimenez J, Riveron-Negrete L, Abdullaev F, Espinosa-Aguirre J, Rodriguez-Arnaiz R (2008) Cytotoxicity of the beta-carboline alkaloids harmine and harmaline in human cell assays in vitro. Exp Toxicol Pathol 60: 381-389. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=18430551.
55. Pin F, Buron F, Saab F, Colliandre L, Bourg S, et al. (2011) Synthesis and biological evaluation of 2,3-bis(het)aryl-4-azaindole derivatives as protein kinase inhibitors. Medchemcomm 2: 899-903.
56. Tahtouh T, Elkins JM, Filippakopoulos P, Soundararajan M, Burgy G, et al. (2012) Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B. J Med Chem 55: 9312-9330.
57. Akue-Gedu R, Debiton E, Ferandin Y, Meijer L, Prudhomme M, et al. (2009) Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins. Bioorg Med Chem 17: 4420-4424. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=19477650.
58. Koo KA, Kim ND, Chon YS, Jung M-SS, Lee B-JJ, et al. (2009) QSAR analysis of pyrazolidine-3,5-diones derivatives as Dyrk1A inhibitors. Bioorg Med Chem Lett 19: 2324-2328. Available: http://www.ncbi.nlm.nih.gov/pubmed/19282176. Accessed: 17 Jul 2012.
59. Loidreau Y, Marchand P, Dubouilh-Benard C, Nourrisson MR, Duflos M, et al. (2012) Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d] pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors. Eur J Med Chem 58C: 171-183. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 23124214.
60. Debray J, Bonte S, Lozach O, Meijer L, Demeunynck M (2012) Catalyst-free synthesis of quinazolin-4-ones from (hetero)aryl-guanidines: application to the synthesis of pyrazolo[4,3-f]quinazolin-9-ones, a new family of DYRK1A inhibitors. Mol Divers 16: 659-667. Available: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list-uids= 22991074.
61. Anderson K, Chen Y, Chen Z, Dominique R, Glenn K, et al. (2013) Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med Chem Lett 23: 6610-6615. Available: http://www.sciencedirect.com/science/article/pii/S0960894X13012614.
62. Cuny GD, Robin M, Ulyanova NP, Patnaik D, Pique V, et al. (2010) Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorg Med Chem Lett 20: 3491-3494. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=20836251.
63. Fröhner W, Lopez-Garcia L a, Neimanis S, Weber N, Navratil J, et al. (2011) 4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKCf. J Med Chem 54: 6714-6723. Available: http://www.ncbi.nlm.nih.gov/pubmed/21863889.
64. Hoppstädter J, Diesel B, Eifler LK, Schmid T, Brüne B, et al. (2012) Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation. Eur J Immunol 42: 1282-1293. Available: http://dx.doi.org/10.1002/eji.201142081.
65. Du C, Huang T, Sun D, Mo Y, Feng H, et al. (2011) CDH4 as a novel putative tumor suppressor gene epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma. Cancer Lett 309: 54-61. Available: http://linkinghub.elsevier.com/retrieve/pii/S0304383511002825?showall=true.
66. Urbich C, Rössig L, Kaluza D, Potente M, Boeckel J-N, et al. (2009) HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells. Blood 113: 5669-5679. Available: http://www.ncbi.nlm.nih.gov/pubmed/19351956. Accessed: 21 Nov 2013.
67. Spandidos A, Wang X, Wang H, Seed B (2010) PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res 38: D792-D799. Available: http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2808898&tool= pmcentrez&rendertype=abstract. Accessed: 11 Nov 2013.
68. Yara S, Lavoie J-C, Beaulieu J-F, Delvin E, Amre D, et al. (2013) Iron-ascorbate-mediated lipid peroxidation causes epigenetic changes in the antioxidant defense in intestinal epithelial cells: impact on inflammation. PLoS One 8: e63456. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=3661745&tool=pmcentrez&rendertype=abstract. Accessed: 1 Dec 2013.
69. Wang K-K, Liu N, Radulovich N, Wigle D a, Johnston MR, et al. (2002) Novel candidate tumor marker genes for lung adenocarcinoma. Oncogene 21: 7598-7604. Available: http://www.ncbi.nlm.nih.gov/pubmed/12386823. Accessed: 3 Dec 2013.
70. Bey E, Marchais-Oberwinkler S, Werth R, Negri M, Al-Soud YA, et al. (2008) Design, synthesis, biological evaluation and pharmacokinetics of bis(hydroxyphenyl) substituted azoles, thiophenes, benzenes, and aza-benzenes as potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1). J Med Chem 51: 6725-6739. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=18855374.
71. Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27: 1350-1359. Available: http://www.ncbi.nlm.nih.gov/pubmed/10534321.
72. Kato R, Gillette J (1965) Effect of Starvation on NADPH-Dependant Enzymes in Liver Microsomes of Male and Female Rats. J Pharmacol Exp Ther 150: 279-284.
73. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10: 1093-1095. (Pubitemid 23211439)
74. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, et al. (2003) A Point-Charge Force Field for Molecular Mechanics Simulations of Proteins Based on Condensed-Phase. J Comput Chem 24: 1999-2012.
75. Krieger E, Darden T, Nabuurs SB, Finkelstein A, Vriend G (2004) Making optimal use of empirical energy functions: force-field parameterization in crystal space. Proteins 57: 678-683. Available: http://www.ncbi.nlm.nih.gov/ pubmed/15390263. Accessed: 7 Mar 2013.
76. Avrutina O, Fittler H, Glotzbach B, Kolmar H, Empting M (2012) Between two worlds: a comparative study on in vitro and in silico inhibition of trypsin and matriptase by redox-stable SFTI-1 variants at near physiological pH. Org Biomol Chem 10: 7753-7762. Available: http://www.ncbi.nlm.nih.gov/pubmed/ 22903577. Accessed: 26 Mar 2013.
77. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, et al. (1998) Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function. J Comput Chem 19: 1639-1662. (Pubitemid 128590223)
78. Besselievre F, Mahuteau-Betzer F, Grierson DS, Piguel S (2008) Ligandless Microwave-Assisted Pd/Cu-Catalyzed Direct Arylation of Oxazoles. J Org chem 73: 3278-3280. Available: http://dx.doi.org/10.1021/jo7027135.
79. Dondoni A, Fantin G, Fogagnolo M, Medici A (1988) Synthesis of (Trimethylsily1)thiazoles and Reactions with Carbonyl Compounds. Selectivity Aspects and Synthetic Utility'. J Org Chem 3: 1748-1761.
80. Primas N, Bouillon A, Lancelot J-C, El-Kashef H, Rault S (2009) Synthesis of 5-arylthiazoles. Comparative study between Suzuki cross-coupling reaction and direct arylation. Tetrahedron 65: 5739-5746. Available: http://linkinghub. elsevier.com/retrieve/pii/S0040402009007121. Accessed: 28 Mar 2013.
81. Bain J, McLauchlan H, Elliott M, Cohen P (2003) The specificities of protein kinase inhibitors: an update. Biochem J 371: 199-204. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1223271&tool= pmcentrez&rendertype=abstract.
82. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol 29: 1039-1045. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= PubMed&dopt=Citation&list-uids=22037377.
83. Wager TT, Chandrasekaran RY, Hou X, Troutman MD, Verhoest PR, et al. (2010) Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes. ACS Chem Neurosci 1: 420-434.
84. Ogawa Y, Nonaka Y, Goto T, Ohnishi E, Hiramatsu T, et al. (2010) Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat Comm 1: 86. Available: http://www.ncbi.nlm.nih.gov/pubmed/20981014. Accessed: 17 Jul 2012.
85. Miyaura N, Yanagi T, Suzuki A (1981) The Palladium-Catalyzed Cross-Coupling Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases. Synth Comm 11: 513-519.
86. Laurence C, Brameld K a, Graton J, Le Questel J-Y, Renault E (2009) The pK(BHX) database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. J Med Chem 52: 4073-4086. Available: http://www.ncbi.nlm. nih.gov/pubmed/19537797. Accessed: 5 Feb 2013.
87. Bird CW (1992) Heteroaromaticity, 5, a unified aromaticity index. Tetrahedron 48: 335-340. Available: http://linkinghub.elsevier.com/retrieve/pii/ S004040200188145X.
88. Ertl P, Rohde B, Selzer P (2000) Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem 43: 3714-3717. Available: http://www.ncbi.nlm.nih.gov/pubmed/11020286.
89. Yang C, Ji D, Weinstein EJ, Choy E, Hornicek FJ, et al. (2010) The kinase Mirk is a potential therapeutic target in osteosarcoma. Carcinogenesis 31: 552-558. Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= 2847087&tool=pmcentrez&rendertype=abstract. Accessed: 17 Jul 2012.
90. Deng X, Ewton DZ, Friedman E (2009) Mirk/Dyrk1B maintains the viability of quiescent pancreatic cancer cells by reducing levels of reactive oxygen species. Cancer Res 69: 3317-3324. Available: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=2669831&tool=pmcentrez&rendertype=abstract. Accessed: 17 Jul 2012.
91. Rothe G, Valet G (1990) Flow cytometric analysis of respiratory burst activity in phagocytes with hydroethidine and 29,79-dichlorofluorescin. J Leukoc Biol 47: 440-448. Available: http://www.jleukbio.org/content/47/5/440.abstract.
92. Deng X, Ewton DZ, Li S, Naqvi A, Mercer SE, et al. (2006) The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma. Cancer Res 66: 4149-4158. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=16618736.
93. Deng X, Ewton DZ, Mercer SE, Friedman E (2005) Mirk/dyrk1B decreases the nuclear accumulation of class II histone deacetylases during skeletal muscle differentiation. J Biol Chem 280: 4894-4905. Available: http://www.ncbi.nlm.nih. gov/pubmed/15546868. Accessed: 3 Dec 2013.
94. Gao J, Yang X, Yin P, Hu W, Liao H, et al. (2012) The involvement of FoxO in cell survival and chemosensitivity mediated by Mirk/Dyrk1B in ovarian cancer. Int J Oncol 40: 1203-1209. Available: http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=3584584&tool=pmcentrez&rendertype=abstract. Accessed: 21 Nov 2013.
95. Bartholome A, Kampkötter A, Tanner S, Sies H, Klotz L-O (2010) Epigallocatechin gallate-induced modulation of FoxO signaling in mammalian cells and C. elegans: FoxO stimulation is masked via PI3K/Akt activation by hydrogen peroxide formed in cell culture. Arch Biochem Biophys 501: 58-64. Available: http://www.sciencedirect.com/science/article/pii/S0003986110002018.
96. Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, et al. (1999) Mitochondrial disease in superoxide dismutase 2 mutant mice. PNAS 96: 846-851. Available: http://www.pnas.org/content/96/3/846.abstract.
97. Pagano MA, Bain J, Kazimierczuk Z, Sarno S, Ruzzene M, et al. (2008) The selectivity of inhibitors of protein kinase CK2: an update. Biochem J 415: 353-365. Available: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve&db=PubMed&dopt=Citation&list-uids=18588507.
98. Wang D, Wang F, Tan Y, Dong L, Chen L, et al. (2012) Discovery of potent small molecule inhibitors of DYRK1A by structure-based virtual screening and bioassay. Bioorg Med chem Lett 22: 168-171. Available: http://www.ncbi.nlm.nih. gov/pubmed/22154664. Accessed: 20 Jun 2013.
99. Grzmil M, Morin P, Lino MM, Merlo A, Frank S, et al. (2011) MAP kinase-interacting kinase 1 regulates SMAD2-dependent TGF-b signaling pathway in human glioblastoma. Cancer Res 71: 2392-2402. Available: http://www.ncbi.nlm. nih.gov/pubmed/21406405. Accessed: 2 Oct 2013.
100. Teague S, Davis A, Leeson P, Oprea T (1999) The Design of Leadlike Combinatorial Libraries. Angew Chem (Int Ed) 38: 3743-3748. Available: http://www.ncbi.nlm.nih.gov/pubmed/10649345.