Identification and characterization of small molecules as potent and specific EPAC2 antagonists

Journal of Medicinal Chemistry

Volumn 56, Issue 3, 2013, Pages 952-962

  Chen, Haijun ^a   Tsalkova, Tamara ^a   Chepurny, Oleg G ^b   Mei, Fang C ^a   Holz, George G ^b   Cheng, Xiaodong ^a   Zhou, Jia ^a  

^a University of Texas Medical Branch School of Medicine   (United States)

^b State University of New York Upstate Medical University: College of Medicine   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(2,5 DICHLOROPHENYL) (2,4,6 TRIMETHYLPHENYL)AMINE; (3,5 DICHLOROPHENYL) (2,4,6 TRIMETHYLPHENYL)AMINE; (4,5 DIMETHYLTHIAZOL 2 YL) (2,4,6 TRIMETHYLPHENYL)AMINE; 1,3,5 TRIMETHYL 2 (2,4,5 TRIMETHYLBENZENESULFONYL)BENZENE; 1,3,5 TRIMETHYL 2 (4 PENTYLBENZENESULFONYL)BENZENE; 2 (4 CYCLOHEXYLBENZENESULFONYL) 1,3,5 TRIMETHYLBENZENE; 2 (4 CYCLOHEXYLOXYBENZENESULFONYL) 1,3,5 TRIMETHYLBENZENE; 2 (4 IODOBENZENESULFONYL) 1,3,5 TRIMETHYLBENZENE; 2 (4 METHOXYBENZENESULFONYL) 1,3,5 TRIMETHYLBENZENE; 2 [4 (2,4,6 TRIMETHYLBENZENESULFONYL)PHENOXY]ETHYLAMINE; 2 ETHYL 1 (2,4,6 TRIMETHYLBENZENESULFONYL) 1 H PYRROLE; 2 ETHYL 1 (4 METHOXYBENZENESULFONYL) 1 H PYRROLE; 2 ETHYL 1 (TOLUENE 4 SULFONYL) 1 H PYRROLE; 2 FLUORO 5 [4 (2,4,6 TRIMETHYLBENZENESULFONYL)PHENYL]PYRIDINE; 2,4 DIMETHYL 1 (2,4,6 TRIMETHYLBENZENESULFONYL) 1 H PYRROLE; 4 (2,4,6 TRIMETHYLBENZENESULFONYL)PHENOL; 4 [4 (2,4,6 TRIMETHYLBENZENESULFONYL)PHENOXY]PIPERIDINE; 4 [4 (2,4,6 TRIMETHYLBENZENESULFONYL)PHENOXY]PIPERIDINE 1 CARBOXYCLIC ACID TERT BUTYL ESTER; 4 TOLYL (2,4,6 TRIMETHYLPHENYL)AMINE; ARYLSULFONAMIDE DERIVATIVE; CYCLIC AMP; DIARYLSULFONE DERIVATIVE; EPAC1 PROTEIN; EPAC2 PROTEIN; ESI 05; GUANINE NUCLEOTIDE EXCHANGE FACTOR; HJC 0350; N,N DIARYLAMINE DERIVATIVE; PROTEIN INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; CELL STRAIN HEK293; DRUG DESIGN; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; IC 50; MITSUNOBU REACTION; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

GUANINE NUCLEOTIDE EXCHANGE FACTORS; HUMANS; INHIBITORY CONCENTRATION 50; MAGNETIC RESONANCE SPECTROSCOPY; SMALL MOLECULE LIBRARIES; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84873887299     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm3014162     Document Type: Article

References (34)

1. Frye, S. V. The art of the chemical probe Nat. Chem. Biol. 2010, 6, 159-161
2. Beavo, J. A.; Brunton, L. L. Cyclic nucleotide research-still expanding after half a century Nat. Rev. Mol. Cell Biol. 2002, 3, 710-718
3. de Rooij, J.; Zwartkruis, F. J.; Verheijen, M. H.; Cool, R. H.; Nijman, S. M.; Wittinghofer, A.; Bos, J. L. EPAC is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP Nature 1998, 396, 474-477
4. Kawasaki, H.; Springett, G. M.; Mochizuki, N.; Toki, S.; Nakaya, M.; Matsuda, M.; Housman, D. E.; Graybiel, A. M. A family of cAMP-binding proteins that directly activate Rap1 Science 1998, 282, 2275-2279
5. Bos, J. L. EPAC: a new cAMP target and new avenues in cAMP research Nat. Rev. Mol. Cell Biol. 2003, 4, 733-738
6. Cheng, X.; Ji, Z.; Tsalkova, T.; Mei, F. C. EPAC and PKA: a tale of two intracellular cAMP receptors Acta Biochim. Biophys. Sin. 2008, 40, 651-662
7. Bos, J. L. EPAC proteins: multi-purpose cAMP targets Trends Biochem. Sci. 2006, 31, 680-686
8. Gloerich, M.; Bos, J. L. EPAC: defining a new mechanism for cAMP action Annu. Rev. Pharmacol. Toxicol. 2010, 50, 355-375
9. Grandoch, M.; Roscioni, S. S.; Schmidt, M. The role of EPAC proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function Br. J. Pharmacol. 2010, 159, 265-284
10. Breckler, M.; Berthouze, M.; Laurent, A. C.; Crozatier, B.; Morel, E.; Lezoualc'h, F. Rap-linked cAMP signaling EPAC proteins: compartmentation, functioning and disease implications Cell. Signalling 2011, 23, 1257-1266
11. Holz, G. G.; Kang, G.; Harbeck, M.; Roe, M. W.; Chepurny, O. G. Cell physiology of cAMP sensor EPAC J. Physiol. 2006, 577, 5-15
12. Holz, G. G; Chepurny, O. G; Schwede, F. EPAC-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors Cell Signalling 2008, 20, 10-20
13. Rehmann, H.; Schwede, F.; Døskeland, S. O.; Wittinghofer, A.; Bos, J. L. Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor EPAC J. Biol. Chem. 2003, 278, 38548-38556
14. Dao, K. K.; Teigen, K.; Kopperud, R.; Hodneland, E.; Schwede, F.; Christensen, A. E.; Martinez, A.; Døskeland, S. O. EPAC1 and cAMP-dependent protein kinase holoenzyme have similar cAMP affinity, but their cAMP domains have distinct structural features and cyclic nucleotide recognition J. Biol. Chem. 2006, 281, 21500-21511
15. Das, R.; Chowdhury, S.; Mazhab-Jafari, M. T.; Sildas, S.; Selvaratnam, R.; Melacini, G. Dynamically driven ligand selectivity in cyclic nucleotide binding domains J. Biol. Chem. 2009, 284, 23682-23696
16. Selvaratnam, R.; Chowdhury, S.; VanSchouwen, B.; Melacini, G. Mapping allostery through the covariance analysis of NMR chemical shifts Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6133-6138
17. Tsalkova, T.; Mei, F. C.; Cheng, X. A fluorescence-based high-throughput assay for the discovery of exchange protein directly activated by cyclic AMP (EPAC) antagonists PLoS One 2012, 7, e30441
18. Chen, H.; Tsalkova, T.; Mei, F. C.; Hu, Y.; Cheng, X.; Zhou, J. 5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP Bioorg. Med. Chem. Lett. 2012, 22, 4038-4043
19. Almahariq, M.; Tsalkova, T.; Mei, F. C.; Chen, H.; Zhou, J.; Sastry, S. K.; Schwede, F.; Cheng, X. A novel EPAC specific inhibitor suppresses pancreatic cancer cell migration and invasion Mol. Pharmacol. 2013, 83, 122-128
20. Tsalkova, T.; Mei, F. C.; Li, S.; Chepurny, O. G.; Leech, C. A.; Liu, T.; Holz, G. G.; Woods, V. L., Jr.; Cheng, X. Isoform-specific antagonists of exchange proteins directly activated by cAMP Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 18613-18618
21. Tsalkova, T.; Blumenthal, D. K.; Mei, F. C.; White, M. A.; Cheng, X. Mechanism of EPAC activation: structural and functional analyses of EPAC2 hinge mutants with constitutive and reduced activities J. Biol. Chem. 2009, 284, 23644-23651
22. Li, S.; Tsalkova, T.; White, M. A.; Mei, F. C.; Liu, T.; Wang, D.; Woods, V. L., Jr.; Cheng, X. Mechanism of intracellular cAMP sensor EPAC2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS) J. Biol. Chem. 2011, 286, 17889-17897
23. Cheng, X.; Phelps, C.; Taylor, S. S. Differential binding of cAMP-dependent protein kinase regulatory subunit isoforms Ialpha and IIbeta to the catalytic subunit J. Biol. Chem. 2001, 276, 4102-4108
24. Yu, S.; Mei, F. C.; Lee, J. C.; Cheng, X. Probing cAMP-dependent protein kinase holoenzyme complexes I alpha and II beta by FT-IR and chemical protein footprinting Biochemistry 2004, 43, 1908-1920
25. Herbst, K. J.; Coltharp, C.; Amzel, L. M.; Zhang, J. Direct activation of EPAC by sulfonylurea is isoform selective Chem. Biol. 2011, 18, 243-251
26. Allen, M. D.; Zhang, J. Subcellular dynamics of protein kinase A activity visualized by FRET-based reporters Biochem. Biophys. Res. Commun. 2006, 348, 716-721
27. Holz, G. G. EPAC: a new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell Diabetes 2004, 53, 5-13
28. Zhang, C. L.; Katoh, M.; Shibasaki, T.; Minami, K.; Sunaga, Y.; Takahashi, H.; Yokoi, N.; Iwasaki, M.; Miki, T.; Seino, S. The cAMP sensor EPAC2 is a direct target of antidiabetic sulfonylurea drugs Science 2009, 325, 607-610
29. Morel, E.; Marcantoni, A.; Gastineau, M.; Birkedal, R.; Rochais, F.; Garnier, A.; Lompre, A. M.; Vandecasteele, G.; Lezoualc'h, F. cAMP-binding protein EPAC induces cardiomyocyte hypertrophy Circ. Res. 2005, 97, 1296-1304
30. Metrich, M.; Lucas, A.; Gastineau, M.; Samuel, J. L.; Heymes, C.; Morel, E.; Lezoualc'h, F. EPAC mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy Circ. Res. 2008, 102, 959-965
31. Lissitzky, J. C.; Parriaux, D.; Ristorcelli, E.; Verine, A.; Lombardo, D.; Verrando, P. Cyclic AMP signaling as a mediator of vasculogenic mimicry in aggressive human melanoma cells in vitro Cancer Res. 2009, 69, 802-809
32. van den Berghe, N.; Cool, R. H.; Horn, G.; Wittinghofer, A. Biochemical characterization of C3G: an exchange factor that discriminates between Rap1 and Rap2 and is not inhibited by Rap1A(S17N) Oncogene 1997, 15, 845-850
33. Cook, P. F.; Neville, M. E., Jr.; Vrana, K. E.; Hartl, F. T.; Roskoski, R., Jr. Adenosine cyclic 3′,5′-monophosphate dependent protein kinase: kinetic mechanism for the bovine skeletal muscle catalytic subunit Biochemistry 1982, 21, 5794-5799
34. Chepurny, O. G.; Leech, C. A.; Kelley, G. G.; Dzhura, I.; Dzhura, E.; Li, X.; Rindler, M. J.; Schwede, F.; Genieser, H. G.; Holz, G. G. Enhanced Rap1 activation and insulin secretagogue properties of an acetoxymethyl ester of an EPAC-selective cyclic AMP analog in rat INS-1 cells: studies with 8-pCPT-2′-O-Me-cAMP-AM J. Biol. Chem. 2009, 284, 10728-10736