Low-molecular-weight MK2 inhibitors: A tough nut to crack!

Future Medicinal Chemistry

Volumn 1, Issue 7, 2009, Pages 1243-1257

  Schlapbach, Achim ^a   Huppertz, Christine ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOCYANOPYRIDINE; AROMATIC AMIDE; CARBOLINE DERIVATIVE; DIHYDROPYRIMIDO[6,1 ALPHA]ISOQUINOLIN 4 ONE; HEAT SHOCK PROTEIN 27; INDAZOLE CARBOXAMIDE; INDAZOLE DERIVATIVE; INDOLOPYRAZINONE; ISOQUINOLINE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE P38; MITOGEN ACTIVATED PROTEIN KINASE P38 INHIBITOR; PYRAZOLE; PYRAZOLO[1,5 A]PYRIMIDINE DERIVATIVE; PYRIDINE DERIVATIVE; PYRIDONE DERIVATIVE; PYRROLOPYRIDONE; PYRROLOPYRIMIDONE; SMALL HEAT SHOCK PROTEIN; SQUARIC ACID DERIVATIVE; TETRAHYDRO BETA CARBOLINE 1 CARBOXYLIC ACID; THIENOPYRIDINE DERIVATIVE; TRYPTOLINE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; COMPETITIVE INHIBITION; CYTOKINE RELEASE; DRUG CONFORMATION; DRUG TARGETING; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN SYNTHESIS; REVIEW; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; ANIMALS; ANTI-INFLAMMATORY AGENTS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MOLECULAR WEIGHT; PATENTS AS TOPIC; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; RATS; TUMOR NECROSIS FACTOR-ALPHA;

EID: 77953397222     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.09.98     Document Type: Review

References (52)

1. Lee JC, Laydon JT, McDonnell PC et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739-746 (1994).
2. Han J, Lee JD, Bibbs I, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808-811 (1994).
3. Saklatvala J. The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr. Opin. Pharmacol. 4, 372-377 (2004).
4. Freshney NM, Rawlinson L, Guesdon F et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039-1049 (1994).
5. Rouse J, Cohen P, Trigon S et al. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78, 1027-1037 (1994).
6. Duraisamy S, Bajpai M, Bughani U, Dastidar SG, Ray A, Chopra P. MK2: a novel molecular target for anti-inflammatory therapy. Expert Opin. Ther. Targets 12, 921-936 (2008).
7. Ronkina N, Kotlyarov A, Gaestel M. MK2 and MK3 - a pair of isoenzymes? Frontiers Biosci. 13, 5511-5521 (2008).
8. Huang CK, Zhan I, Ai Y, Jongstra J. LSP-1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. J. Biol. Chem. 272, 17-29 (1997).
9. Kotlyarov A, Neininger A, Schubert C et al. MAPKAP kinase 2 is essential for LPSinduced TNFa biosynthesis. Nat. Cell. Biol. 1, 94-97 (1999).
10. Hegen M, Gaestel M, Nickerson-Nutter CL, Lin L-L, Telliez J-B. MAPKAP kinase 2-deficient mice are resistant to collageninduced arthritis. J. Immunol. 177, 1913-1917 (2006).
11. Gorska MM, Liang Q, Stafford SJ et al. MK2 controls the level of negative feedback in the NF-kB pathway and is essential for vascular permeability and airway inflammation. J. Exp. Med. 204, 1637-1652 (2007).
12. Funding AT, Johansen C, Gaestel M et al. Reduced oxazolone-induced skin inflammation in MAPKAP kinase 2 knockout mice. J. Invest. Dermatol. 129, 891-898 (2009).
13. Tietz AB, Malo A, Diebold J, Gaestel M, Goeke B, Schaefer C. Gene deletion of MK2 inhibits TNF-a and IL-6 and protects against cerulein-induced pancreatitis. Am. J. Physiol. Gastroint. Liver Physiol. 290, 1298-1306 (2006).
14. Jagavelu K, Tietge UJ, Gaestel M, Drexler H, Schieffer B, Bavendiek U. Systemic deficiency of the MAP kinase-activated protein kinase 2 reduces atherosclerosis in hypercholesterolemic mice. Circ. Res. 101, 1104-1112 (2007).
15. Nagy N, Shiroto G, Malik CK et al. Ischemic preconditioning involves dual cardioprotective axes with p38MAPK as upstream target. J. Mol. Cell Cardiol. 42, 981-990 (2007).
16. Wang X, Xu L, Wang P, Young R, Gaestel M, Feuerstein GZ. Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 deficiency protects brain from ischemic injury in mice. J. Biol. Chem. 277, 43968-43972 (2002).
17. Thomas T, Timmer M, Cesnulevicius K, Hitti E, Kotlyarov A, Gaestel M. MAPKAP kinase 2-deficiency prevents neurons from cell death by reducing neuroinflammation - relevance in a mouse model of Parkinson's disease. J. Neurochem. 105, 2039-2052 (2008).
18. Culbert AA, Skaper SD, Howlett DR et al. MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. J. Biol. Chem. 281, 23658-23667 (2006).
19. Kotlyarov A, Yannoni Y, Fritz S et al. Distinct cellular functions of MK2. Mol. Cell. Biol. 22, 4827-4835 (2002).
20. Johansen C, Toftegaard AF, Otkjaer C et al. Protein expression of TNF-a in psoriatic skin is regulated at a posttranscriptional level by MAPK-activated protein kinase 2. J. Immunol. 176, 1431-1438 (2006).
21. Miyazawa K, Mori A, Miyata H, Akahane M, Ajisawa Y, Okudaira H. Regulation of interleukin-1b-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase. J. Biol. Chem. 273, 24832-24838 (1998).
22. Schett G, Zwerina J, Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann. Rheum. Diss. 67, 909-916 (2008).
23. Ronkina N, Kotlyarov A, Dittrich-Breiholz O et al. 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. 27, 170-181 (2007).
24. Anderson DR, Hegde S, Reinhard E et al. Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK2). Bioorg. Med. Chem. Lett. 15, 1587-1590 (2005).
25. Anderson DR, Meyers MJ, Vernier WF et al. Pyrrolopyridine inhibitors of mitogenactivated protein kinase-activated protein Kinase 2 (MK-2). J. Med. Chem. 50, 2647-2654 (2007).
26. Hillig CH, Eberspaecher U, Monteclaro F et al. Structural basis for high affinity inhibitor bound to protein kinase MK2. J. Mol. Biol. 369, 735-745 (2007).
27. Schlapbach A, Feifel R, Hawtin S et al. Pyrrolopyrimidones: a novel class of MK2 inhibitors with potent cellular activity. Bioorg. Med. Chem. Lett. 18, 6142-6146 (2008)
28. Trujillo JI, Meyers MJ, Anderson DR et al. Novel tetrahydro-b-carboline- 1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase (MK-2), Bioorg. Med. Chem. Lett. 17, 4657-4663 (2007).
29. Wu J-P, Wang J, Abeywardane A et al. The discovery of carboline analogs as potent MAPKAP-K2 inhibitors. Bioorg. Med. Chem. Lett. 17, 4664-4669 (2007).
30. Goldberg DR, Choi Y, Cogan D et al. Pyrazinoindolone inhibitors of MAPKAP-K2. Bioorg. Med. Chem. Lett. 18, 938-941 (2008).
31. Xiong Z, Gao DA, Cogan DA et al. Synthesis and SAR studies of indole-based MK2 inhibitors. Bioorg. Med. Chem. Lett. 18, 1994-1999 (2008).
32. Lovering F, Kirincich S, Wang W et al. Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg. Med. Chem. 17, 3342-3351 (2009).
33. Dumitru CD, Ceci JD, Tsatsanis C et al. TNF-a induction by LPS is regulated posttranscriptionally via a Tpl2/ERKdependent pathway. Cell 103, 1071-1083 (2000).
34. Cohen P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr. Op. Cell Biol. 21, 317-324 (2009).
35. Lord KA, Creasy AGK, King C, Burns BM, Lee JC, Dillon SB. REDK, a novel human regulatory erythroid kinase. Blood 95, 2838-2846 (2000).
36. Constantine KL, Mueller L, Metzler WJ et al. Multiple and single binding modes of fragment-like kinase inhibitors revealed by molecular modeling, residue typeselective protonation, and nuclear Overhauser effects. J. Med. Chem. 51, 6225-6229 (2008).
37. Jahnke J. Fragment-based approaches. In: Comprehensive Medicinal Chemistry II (Volume 3). Taylor JB, Tiggle DJ (Eds). Elsevier Ltd, Oxford, UK, 939-957 (2006).
38. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95-105 (2000).
39. Gschwendt M, Muller HJ, Kielbassa K et al. Rottlerin: a novel protein kinase inhibitor. Biochem. Biophys. Res. Commun. 199, 93-98 (1994).
40. Soltoff SP: Rottlerin: an inappropriate and ineffective inhibitor of PKCd. Trends Pharmacol. Sci. 28, 453-458 (2007).
41. Williams DE, Telliez J-B, Liu J, Tahir A, van Soest R, Andersen RJ. Meroterpenoid MAPKAP (MK2) inhibitors isolated from the Indonesian marine sponge Acathodendrilla sp. J. Nat. Prod. 67, 2127-2129 (2004).
42. Graziani EI, Ritacco FV, Bernan VS, Telliez J-B. Phaeeochromycins A-E: anti-inflammatory polyketides isolated from the soil actinomycete Streptomyces phaeochromogenes LL-P018. J. Nat. Prod. 68, 1262-1265 (2005).
43. Lukas SM, Kroe RR, Wildeson J et al. Catalysis and function of the p38a-MK2a signalling complex. Biochemistry 43, 9950-9960 (2004).
44. Meng W, Swenson LL, Fitzgibbon MJ et al. Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activity with nuclear export. J. Biol. Chem. 277, 37401-37406 (2002).
45. Davidson W, Frego L, Peet GW et al. Discovery and characterization of a substrate selective p38a inhibitor. Biochemistry 43, 11658-11671 (2004).
46. Davis T, Bagley MC, Dix MC et al. Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38a MAPK inhibitors in Werner syndrome cells. Bioorg. Med. Chem. Lett. 17, 6832-6835 (2007).
47. Almholt DLC, Loechel F, Nielsen SJ et al. Nuclear export inhibitors and kinase inhibitors identified using a MAPKactivated protein kinase 2 redistribution® screen. Assay Drug Dev. Tech. 2, 7-20 (2004).
48. White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT. Molecular basis of MAPK-activated protein kinase 2: p38 assembly. Proc. Nat. Acad. Sci. USA 104, 6353-6358 (2007).
49. ter Haar E, Prabhakar P, Liu X, Lepre C. Crystal structure of the p38a-MAPKAP kinase 2 heterodimer. J. Biol. Chem. 282, 9733-9739 (2007).
50. Underwood KW, Parris KD, Federico E et al. Catalytically active MAPKAP kinase 2 structures in complex with staurosporine and ADP reveals differences with the autoinhibited enzyme. Structure 11, 627-636 (2003).
51. Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 60, 317-320 (2009).
52. Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signaling in inflammation. Nat. Rev. Drug Disc. 8, 480-499 (2009)