Discovery of N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as highly active and selective SGK1 inhibitors

ACS Medicinal Chemistry Letters

Volumn 6, Issue 1, 2015, Pages 73-78

  Halland, Nis ^a   Schmidt, Friedemann ^a   Weiss, Tilo ^a   Saas, Joachim ^a   Li, Ziyu ^a   Czech, Jörg ^a   Dreyer, Matthias ^a   Hofmeister, Armin ^a   Mertsch, Katharina ^a   Dietz, Uwe ^a   Strübing, Carsten ^a   Nazare, Marc ^b  

^a Sanofi R and D   (Germany)

^b LEIBNIZ INSTITUT FÜR MOLEKULARE PHARMAKOLOGIE   (Germany)

Author keywords

AGC kinase; Serum glucocorticoid regulated kinase; virtual screening; WNT signaling

Indexed keywords

1H PYRAZOLO[3,4 B]PYRAZIN 3 AMINE; PROTEIN SERINE THREONINE KINASE INHIBITOR; PYRAZINE DERIVATIVE; SERUM AND GLUCOCORTICOID REGULATED KINASE 1; SULFONAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG ABSORPTION; DRUG CLEARANCE; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IN VITRO STUDY; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION;

EID: 84920747930     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml5003376     Document Type: Article

References (32)

1. Bruhn, M. A.; Pearson, R. B.; Hannan, R. D.; Sheppard, K. E. Second AKT: the rise of SGK in cancer signalling. Growth Factors 2010, 28, 394.
2. Hong, F.; Larrea, M. D.; Doughty, C.; Kwiatkowski, D. J.; Squillace, R.; Slingerland, J. M. mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation. Mol. Cell 2008, 30, 701.
3. Lang, F.; Artunc, F.; Vallon, V. The physiological impact of the serum and glucocorticoid-inducible kinase SGK1. Curr. Opin. Nephrol. Hypertens. 2009, 18, 439.
4. Lang, F.; Bohmer, C.; Palmada, M.; Seebohm, G.; Strutz-Seebohm, N.; Vallon, V. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol. Rev. 2006, 86, 1151.
5. Lang, F.; Görlach, A. Heterocyclic indazole derivatives as SGK1 inhibitors, WO2008138448. Expert Opin. Ther. Pat 2010, 2, 129-35.
6. Anacker, C.; Cattaneo, A.; Musaelyan, K.; Zunszain, P. A.; Horowitz, M.; Molteni, R.; Luoni, A.; Calabrese, F.; Tansey, K.; Gennarelli, M.; Thuret, S.; Price, J.; Uher, R.; Riva, M. A.; Pariante, C. M. Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proc. Natl. Acad. Sci. 2013, 110, 8708.
7. Dehner, M.; Hadjihannas, M.; Weiske, J.; Huber, O.; Behrens, J. Wnt signaling inhibits Forkhead box O3a-induced transcription and apoptosis through up-regulation of serum- and glucocorticoid-inducible kinase 1. J. Biol. Chem. 2008, 283, 19201.
8. Sopjani, M.; Alesutan, I.; Wilmes, J.; Dermaku-Sopjani, M.; Lam, R. S.; Koutsouki, E.; Jakupi, M.; Foller, M.; Lang, F. Stimulation of Na+/K+ ATPase activity and Na+ coupled glucose transport by β-catenin. Biochem. Biophys. Res. Commun. 2010, 402, 467.
9. BelAiba, R. S.; Djordjevic, T.; Bonello, S.; Artunc, F.; Lang, F.; Hess, J.; Gorlach, A. The kinase Sgk-1 is involved in pulmonary vascular remodeling. Circ. Res. 2006, 98, 828.
10. Stevens, V. A.; Saad, S.; Poronnik, P.; Fenton-Lee, C. A.; Polhill, T. S.; Pollock, C. A. The role of SGK-1 in angiotensin II-mediated sodium reabsorption in human proximal tubular cells. Nephrol., Dial., Transplant. 2008, 23, 1834.
11. Thomas, S. V.; Kathpalia, P. P.; Rajagopal, M.; Charlton, C.; Zhang, J.; Eaton, D. C.; Helms, M. N.; Pao, A. C. Epithelial sodium channel regulation by cell surface-associated serum- and glucocorticoid-regulated kinase 1. J. Biol. Chem. 2011, 286, 32074.
12. Voelkl, J.; Mia, S.; Meissner, A.; Ahmed, M. S.; Feger, M.; Elvira, B.; Walker, B.; Alessi, D. R.; Alesutan, I.; Lang, F. PKB/SGK-resistant GSK-3 signaling following unilateral ureteral obstruction. Kidney Blood Press. Res. 2013, 38, 156.
13. Wallace, K.; Long, Q.; Fairhall, E. A.; Charlton, K. A.; Wright, M. C. Serine/threonine protein kinase SGK1 in glucocorticoid-dependent transdifferentiation of pancreatic acinar cells to hepatocytes. J. Cell Sci. 2011, 124, 405.
14. Hammond, M.; Washburn, D. G.; Hoang, H. T.; Manns, S.; Frazee, J. S.; Nakamura, H.; Patterson, J. R.; Trizna, W.; Wu, C.; Azzarano, L. M.; Nagilla, R.; Nord, M.; Trejo, R.; Head, M. S.; Zhao, B.; Smallwood, A. M.; Hightower, K.; Laping, N. J.; Schnackenberg, C. G.; Thompson, S. K. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 4441-4445.
15. Merck patents WO2005/037773, WO2006/105850, WO2005/123688, WO2006/105865.
16. Towhid, S. T.; Liu, G. L.; Ackermann, T. F.; Beier, N.; Scholz, W.; Fuchss, T.; Toulany, M.; Rodemann, H. P.; Lang, F. Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683. Cell. Physiol. Biochem. 2013, 32, 838.
17. Geldenhuys, W. J.; Talasila, P. K.; Sadana, P. Identification of a novel serum and glucocorticoid regulated kinase-1 (SGK1) ligand from virtual screening. Bioorg. Med. Chem. Lett. 2012, 22, 5675.
18. Nazaré, M.; Halland, N.; Schmidt, F.; Weiss, T.; Dietz, U.; Hofmeister, A. WO2013041119.
19. Oprea, T.; Matter, H. Integrating virtual screening in lead discovery. Curr. Opin Chem. Biol. 2004, 8, 349-58.
20. Schneider, G. Virtual screening: an endless staircase? Nat. Rev. Drug Discovery 2010, 9, 273-276.
21. Kruger, D. M.; Evers, A. Comparison of structure- and ligand-based virtual screening protocols considering hit list complementarity and enrichment factors. ChemMedChem 2010, 5, 148-158.
22. After preparation of this letter, structures of other SGK1 inhibitors were published. Ortuso, F.; Amato, R.; Artese, A.; D'antona, L.; Costa, G.; Talarico, C.; Gigliotti, F.; Bianco, C.; Trapasso, F.; Schenone, S.; Musumeci, F.; Botta, L.; Perrotti, N.; Alcaro, S. In silico identification and biological evaluation of novel selective serum/glucocorticoid-inducible kinase 1 inhibitors based on the pyrazolopyrimidine scaffold. J. Chem. Inf. Model. 2014, 54, 1828-1832.
23. Zhao, B.; Lehr, R.; Smallwood, A. M.; Ho, T. F.; Maley, K.; Randall, T.; Head, M. S.; Koretke, K. K.; Schnackenberg, C. G. Crystal Structure of Inactive SGK1 in Complex with AMP-PNP. Protein Sci. 2007, 16, 2761-2769.
24. OpenEye Scienti fic Software; www.eyesopen.com.
25. Bostrom, J.; Greenwood, J. R.; Gottfries, J. Assessing the performance of OMEGA with respect to retrieving bioactive conformations. J. Mol. Graphics Model. 2003, 21, 449-462.
26. Kirchmair, J.; Distinto, S.; Markt, P.; Schuster, D.; Spitzer, G. M.; Liedl, K. R.; Wolber, G. J. How to optimize shape-based virtual screening: choosing the right query and including chemical information. Chem. Inf Model. 2009, 49, 678-92.
27. The compounds were tested for serum glucocorticoid-regulated kinase-1 (SGK1) inhibitory activity in a substrate phosphorylation assay. The phosphorylated substrate peptide and nonphosphorylated peptide are separated with caliper life sciences (PerkinElmer) lab-chip technology based on a microfluidic method. The substrate peptide is attached to a fluo-5(6)-carboxyfluorescein)-RPRAATF-NH2 fluorescent group facilitating detection by laser excitation and readout of the fluorescence signal. Recombinant human SGK1 enzyme was expressed in a baculovirus system and activated by human PDK1.
28. Jester, B. W.; Gaj, A.; Shomin, C. D.; Cox, K. J.; Ghosh, I. Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen. J. Med. Chem. 2012, 55, 1526.
29. Fedorov, O.; Marsden, B.; Pogacic, V.; Rellos, P.; Muller, S.; Bullock, A. N.; Schwaller, J.; Sund-strom, M.; Knapp, S. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 20523.
30. Kirchner, S. Kinases as antitargets in genotoxicity. In Polypharmacology in Drug Discovery; Peters, J. U., Eds.; John Wiley and Sons: New York, 2012.
31. Hasinoff, B. B.; Patel, D. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro. Toxicol. Appl. Pharmacol. 2010, 249 (2), 132-139.
32. Schmidt, F.; Matter, H.; Hessler, G.; Czich, A. Predictive in silico off-target profiling in drug discovery. Future Med. Chem. 2014, 6 (3), 295-317.