2p33 | pdb_00002p33
Synthesis and SAR of Aminopyrimidines as Novel c-Jun N-Terminal Kinase (JNK) Inhibitors
Structural highlights
Disease[MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. Function[MK10_HUMAN] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe development of a series of novel aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, JNK2 and CDK2, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Synthesis and SAR of aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors.,Alam M, Beevers RE, Ceska T, Davenport RJ, Dickson KM, Fortunato M, Gowers L, Haughan AF, James LA, Jones MW, Kinsella N, Lowe C, Meissner JW, Nicolas AL, Perry BG, Phillips DJ, Pitt WR, Platt A, Ratcliffe AJ, Sharpe A, Tait LJ Bioorg Med Chem Lett. 2007 Jun 15;17(12):3463-7. Epub 2007 Mar 30. PMID:17459703[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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