Discovery and hit-to-lead optimization of non-ATP competitive MK2 (MAPKAPK2) inhibitors

ACS Medicinal Chemistry Letters

Volumn 2, Issue 8, 2011, Pages 632-637

  Huang, Xiaohua ^a   Shipps, Gerald W ^a   Cheng, Cliff C ^a   Spacciapoli, Peter ^a   Zhang, Xingmin ^a   McCoy, Mark A ^a   Wyss, Daniel F ^a   Yang, Xianshu ^a   Achab, Abdelghani ^a   Soucy, Kyle ^a   Montavon, Donna K ^a   Murphy, Denise M ^a   Whitehurst, Charles E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

1H 15N HSQC(heteronuclear single quantum coherence); Automated Ligand Identification System (ALIS); Mitogen activated protein kinase activated protein kinase 2; non ATP competitive inhibitors; saturation transfer difference (STD)NMR

Indexed keywords

ADENOSINE TRIPHOSPHATE; FURAN 2 CARBOXYAMIDE; FURAN DERIVATIVE; MAPKAPK2 INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG TARGETING; HUMAN; HUMAN CELL; IN VITRO STUDY; MASS SPECTROMETRY; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RAT; REACTION OPTIMIZATION; STRUCTURE ACTIVITY RELATION;

EID: 80051744356     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml200113y     Document Type: Article

References (32)

1. Tobón, G. J.; Youinou, P.; Saraux, A. The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis Autoimmun. Rev. 2010, 9, A288
2. Kumar, S.; Boehm, J.; Lee, J. C. p38 MAP Kinases: key signalling molecules as therapeutic targets for inflammatory diseases Nat. Rev. Drug Discovery 2003, 2, 717
3. Schindler, J. F.; Monahan, J. B.; Smith, W. G. p38 Pathway kinases as anti-inflammatory drug targets J. Dent. Res. 2007, 86, 800
4. Schett, G.; Zwerina, J.; Firestein, G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis Ann. Rheum. Dis. 2008, 67, 909
5. Alten, R. E.; Zerbini, C.; Jeka, S.; Irazoque, F.; Khatib, F.; Emery, P.; Bertasso, A.; Rabbia, M.; Caulfield, J. P. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy Ann. Rheum. Dis. 2010, 69, 364
6. Dambach, D. M. Potential adverse effects associated with inhibition of p38α/β MAP kinases Curr. Top. Med. Chem. 2005, 5, 929
7. Gaestel, M; Mengel, A.; Bothe, U.; Asadullah, K. Protein kinases as small molecule inhibitor targets in inflammation Curr. Med. Chem. 2007, 14, 2214
8. Duraisamy, S.; Bajpai, M.; Bughani, U.; Dastidar, S. G.; Ray, A.; Chopra, P. MK2: A novel molecular target for anti-inflammatory therapy Expert Opin. Ther. Targets 2008, 12, 921
9. White, A.; Pargellis, C. A.; Studts, J. M.; Werneburg, B. G.; Farmer, B. T., II. Molecular basis of MAPK-activated protein kinase 2:p38 assembly Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 6353
10. Haar, E. T.; Prabhakar, P.; Liu, X.; Lepre, C. Crystal structure of the p38α-MAPKAP kinase 2 heterodimer J. Biol. Chem. 2007, 282, 14684
11. Kotlyarov, A.; Neininger, A.; Schubert, C.; Eckert, R.; Birchmeier, C.; Volk, H.-D.; Gaestel, M. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis Nat. Cell Biol. 1999, 1, 94
12. Shi, Y.; Kotlyarov, A.; Laaß, K.; Gruber, A. D.; Butt, E.; Marcus, K.; Meyer, H. E.; Friedrich, A.; Volk, H.-D.; Gaestel, M. Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination Mol. Cell. Biol. 2003, 23, 7732
13. Ronkina, N.; Kotlyarov, A.; Dittrich-Breiholz, O.; Kracht, M.; Hitti, E.; Milarski, K.; Askew, R.; Marusic, S.; Lin, L.-L.; Gaestel, M.; Telliez, J.-B. The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK Mol. Cell. Biol. 2007, 27, 170
14. Hegen, M.; Gaestel, M.; Nickerson-Nutter, C. L.; Lin, L.-L.; Telliez, J.-B. MAPKAP Kinase 2-deficient mice are resistant to collagen-induced arthritis J. Immunol. 2006, 177, 1913
15. Gorska, M. M.; Liang, Q.; Stafford, S. J.; Goplen, N.; Dharajiya, N.; Guo, L.; Sur, S.; Gaestel, M.; Alam, R. MK2 controls the level of negative feedback in the NF-κB pathway and is essential for vascular permeability and airway inflammation J. Exp. Med. 2007, 204, 1637
16. Basabe, P.; Martín, M.; Bodero, O.; Blanco, A.; Marcos, I. S.; Díez, D.; Urones, J. G. Synthesis of (+)-makassaric acid, a protein kinase MK2 inhibitor Tetrahedron 2010, 66, 6008
17. Argiriadi, M. A.; Ericsson, A. M.; Harris, C. M.; Banach, D. L.; Borhani, D. W.; Calderwood, D. J.; Demers, M. D.; DiMauro, J.; Dixon, R. W.; Hardman, J.; Kwak, S.; Li, B.; Mankovich, J. A.; Marcotte, D.; Mullen, K. D.; Ni, B.; Pietras, M.; Sadhukhan, R.; Sousa, S.; Tomlinson, M. J.; Wang, L.; Xiang, T.; Talanian, R. V. 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode Bioorg. Med. Chem. Lett. 2010, 20, 330
18. Harris, C. M.; Ericsson, A. M.; Argiriadi, M. A.; Barberis, C.; Borhani, D. W.; Burchat, A.; Calderwood, D. J.; Cunha, G. A.; Dixon, R. W.; Frank, K. E.; Johnson, E. F.; Kamens, J.; Kwak, S.; Li, B.; Mullen, K. D.; Perron, D. C.; Wang, L.; Wishart, N.; Wu, X.; Zhang, X.; Zmetra, T. R.; Talanian, R. V. 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization Bioorg. Med. Chem. Lett. 2010, 20, 334
19. Xiong, Z.; Gao, D. A.; Cogan, D. A.; Goldberg, D. R.; Hao, M.-H.; Moss, N.; Pack, E.; Pargellis, C.; Skow, D.; Trieselmann, T.; Werneburg, B.; White, A. Synthesis and SAR studies of indole-based MK2 inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 1994
20. Anderson, D. R.; Meyers, M. J.; Vernier, W. F.; Mahoney, M. W.; Kurumbail, R. G.; Caspers, N.; Poda, G. I.; Schindler, J. F.; Reitz, D. B.; Mourey, R. J. Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2) J. Med. Chem. 2007, 50, 2647
21. Lin, S.; Lombardo, M.; Malkani, S.; Hale, J. J.; Mills, S. G.; Chapman, K.; Thompson, J. E.; Zhang, W. X.; Wang, R.; Cubbon, R. M.; O'Neill, E. A.; Luell, S.; Carballo-Jane, E.; Yang, L. Novel 1-(2-aminopyrazin-3-yl)methyl-2- thioureas as potent inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2) Bioorg. Med. Chem. Lett. 2009, 19, 3238
22. Mourey, R. J.; Burnette, B. L.; Brustkern, S. J.; Daniels, J. S.; Hirsch, J. L.; Hood, W. F.; Meyers, M. J.; Mnich, S. J.; Pierce, B. S.; Saabye, M. J.; Schindler, J. F.; South, S. A.; Webb, E. G.; Zhang, J.; Anderson., D. R. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation J. Pharmacol. Exp. Ther. 2010, 333, 797
23. Olsson, H.; Sjö, P.; Ersoy, O.; Kristoffersson, A.; Larsson, J.; Nordén, B. 4-Anilino-6-phenyl-quinoline inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2) Bioorg. Med. Chem. Lett. 2010, 20, 4738
24. Annis, A.; Chuang, C.-C.; Nazef, N. ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein-Ligand Interactions. In Methods and Principles in Medicinal Chemistry; Wanner, K.; Höfner, G., Eds.; Mass Spectrometry in Medicinal Chemistry: Applications in Drug Discovery; Mannhold, R.; Kubinyi, H.; Folkers, G., Series Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2007; Vol. 36, Chapter 3.
25. Zu, Y.-L.; Ai, Y.; Huang, C.-K. Characterization of an autoinhibitory domain in human mitogen-activated protein kinase-activated protein kinase 2 J. Biol. Chem. 1995, 270, 202
26. Meng, W.; Swenson, L. L.; Fitzgibbon, M. J.; Hayakawa, K.; Haar, E. t.; Behrens, A. E.; Fulghum, J. R.; Lippke, J. A. Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export J. Biol. Chem. 2002, 277, 37401
27. Engel, K.; Kotlyarov, A.; Gaestel, M. Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation EMBO J. 1998, 17, 3363
28. Kervinen, J.; Ma, H.; Bayoumy, S.; Schubert, C.; Milligan, C.; Lewandowski, F.; Moriarty, K.; DesJarlais, R. L.; Ramachandren, K.; Wang, H.; Harris, C. A.; Grasberger, B.; Todd, M.; Springer, B. A.; Deckman, I. Effect of construct design on MAPKAP kinase-2 activity, thermodynamic stability and ligand-binding affinity Arch. Biochem. Biophys. 2006, 449, 47
29. Malawski, G. A.; Hillig, R. C.; Monteclaro, F.; Eberspaecher, U.; Schmitz, A. A. P.; Crusius, K.; Huber, M.; Egner, U.; Donner, P.; Müller-Tiemann, B. Identifying protein construct variants with increased crystallization propensity-A case study Protein Sci. 2006, 15, 2718
30. McCoy, M. A.; Senior, M. M.; Wyss, D. F. Screening of protein kinases by ATP-STD NMR spectroscopy J. Am. Chem. Soc. 2005, 127, 7978
31. Akaike, H. An information criterion (AIC) Math. Sci. 1976, 14, 5
32. Jones, S. W.; Brockbank, S. M. V.; Clements, K. M.; Le Good, N.; Campbell, D.; Read, S. J.; Needham, M. R. C.; Newham, P. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) modulates key biological pathways associated with OA disease pathology Osteoarthritis Cartilage 2009, 17, 124