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|3g9l, resolution 2.20Å ()|
|Gene:||JNK3, JNK3A, MAPK10, PRKM10 (Homo sapiens)|
JNK3 bound to (Z)-1-((6-fluoro-4H-benzo[d][1,3]dioxin-8-yl)methyl)-3-(hydroxyimino)-4-styrylindolin-2-one
A series of N-benzylated isatin oximes were developed as inhibitors of the mitogen-activated kinase, JNK3. X-ray crystallographic structures aided in the design and synthesis of novel, selective compounds, that inhibit JNK3, but not p38 MAP kinase and provided key insights into understanding the behavior of gatekeeper residue methionine-146 in determining target selectivity for this series.
Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors., Cao J, Gao H, Bemis G, Salituro F, Ledeboer M, Harrington E, Wilke S, Taslimi P, Pazhanisamy S, Xie X, Jacobs M, Green J, Bioorg Med Chem Lett. 2009 May 15;19(10):2891-5. Epub 2009 Mar 17. PMID:19361991
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[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.
[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.
About this Structure
- Cao J, Gao H, Bemis G, Salituro F, Ledeboer M, Harrington E, Wilke S, Taslimi P, Pazhanisamy S, Xie X, Jacobs M, Green J. Structure-based design and parallel synthesis of N-benzyl isatin oximes as JNK3 MAP kinase inhibitors. Bioorg Med Chem Lett. 2009 May 15;19(10):2891-5. Epub 2009 Mar 17. PMID:19361991 doi:10.1016/j.bmcl.2009.03.043