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{{STRUCTURE_3rtp|  PDB=3rtp  |  SCENE=  }}
===Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration===
{{ABSTRACT_PUBMED_21813278}}


==Disease==
==Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration==
<StructureSection load='3rtp' size='340' side='right' caption='[[3rtp]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3rtp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RTP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RTP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=34I:N-[4-CYANO-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>34I</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK10, JNK3, JNK3A, PRKM10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rtp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rtp OCA], [http://pdbe.org/3rtp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rtp RCSB], [http://www.ebi.ac.uk/pdbsum/3rtp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rtp ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[http://omim.org/entry/606369 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.  
[[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[http://omim.org/entry/606369 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 ==
[[http://www.uniprot.org/uniprot/MK10_HUMAN 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.<ref>PMID:11718727</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.


==Function==
Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.,Bowers S, Truong AP, Jeffrey Neitz R, Hom RK, Sealy JM, Probst GD, Quincy D, Peterson B, Chan W, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Lin M, Yao N, Artis DR, Zhang H, Chen L, Dryer M, Samant B, Zmolek W, Wong K, Lorentzen C, Goldbach E, Tonn G, Quinn KP, Sauer JM, Wright S, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100., Epub 2011 Jul 7. PMID:21813278<ref>PMID:21813278</ref>
[[http://www.uniprot.org/uniprot/MK10_HUMAN 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.<ref>PMID:11718727</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3rtp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RTP OCA].
</div>
<div class="pdbe-citations 3rtp" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
<references group="xtra"/><references/>
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]]
[[Category: Homo sapiens]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Artis, D R.]]
[[Category: Artis, D R]]
[[Category: Bard, F.]]
[[Category: Bard, F]]
[[Category: Bowers, S.]]
[[Category: Bowers, S]]
[[Category: Chan, W.]]
[[Category: Chan, W]]
[[Category: Chen, L.]]
[[Category: Chen, L]]
[[Category: Dryer, M.]]
[[Category: Dryer, M]]
[[Category: Galemmo, R A.]]
[[Category: Galemmo, R A]]
[[Category: Goldbach, E.]]
[[Category: Goldbach, E]]
[[Category: Griswold-Prenne, I.]]
[[Category: Griswold-Prenne, I]]
[[Category: Hom, R K.]]
[[Category: Hom, R K]]
[[Category: Konradi, A W.]]
[[Category: Konradi, A W]]
[[Category: Lin, M.]]
[[Category: Lin, M]]
[[Category: Lorentzen, C.]]
[[Category: Lorentzen, C]]
[[Category: Neitz, R J.]]
[[Category: Neitz, R J]]
[[Category: Pan, H.]]
[[Category: Pan, H]]
[[Category: Peterson, B.]]
[[Category: Peterson, B]]
[[Category: Powell, K.]]
[[Category: Powell, K]]
[[Category: Probst, G D.]]
[[Category: Probst, G D]]
[[Category: Quincy, Q.]]
[[Category: Quincy, Q]]
[[Category: Quinn, K P.]]
[[Category: Quinn, K P]]
[[Category: Ren, Z.]]
[[Category: Ren, Z]]
[[Category: Ruslim, L.]]
[[Category: Ruslim, L]]
[[Category: Samant, B.]]
[[Category: Samant, B]]
[[Category: Sauer, J.]]
[[Category: Sauer, J]]
[[Category: Sealy, J M.]]
[[Category: Sealy, J M]]
[[Category: Sham, H L.]]
[[Category: Sham, H L]]
[[Category: Tonn, G.]]
[[Category: Tonn, G]]
[[Category: Truong, A P.]]
[[Category: Truong, A P]]
[[Category: Wong, K.]]
[[Category: Wong, K]]
[[Category: Wright, S.]]
[[Category: Wright, S]]
[[Category: Yao, N.]]
[[Category: Yao, N]]
[[Category: Yednock, T A.]]
[[Category: Yednock, T A]]
[[Category: Zhang, H.]]
[[Category: Zhang, H]]
[[Category: Zmolek, W.]]
[[Category: Zmolek, W]]
[[Category: Jnk inhibitor]]
[[Category: Jnk inhibitor]]
[[Category: Neurodegeneration]]
[[Category: Neurodegeneration]]
[[Category: Pharmacokinetic property]]
[[Category: Pharmacokinetic property]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 05:12, 5 August 2016

Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegenerationDesign and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration

Structural highlights

3rtp is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:MAPK10, JNK3, JNK3A, PRKM10 (HUMAN)
Activity:Mitogen-activated protein kinase, with EC number 2.7.11.24
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.

Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.,Bowers S, Truong AP, Jeffrey Neitz R, Hom RK, Sealy JM, Probst GD, Quincy D, Peterson B, Chan W, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Lin M, Yao N, Artis DR, Zhang H, Chen L, Dryer M, Samant B, Zmolek W, Wong K, Lorentzen C, Goldbach E, Tonn G, Quinn KP, Sauer JM, Wright S, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100., Epub 2011 Jul 7. PMID:21813278[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Neidhart S, Antonsson B, Gillieron C, Vilbois F, Grenningloh G, Arkinstall S. c-Jun N-terminal kinase-3 (JNK3)/stress-activated protein kinase-beta (SAPKbeta) binds and phosphorylates the neuronal microtubule regulator SCG10. FEBS Lett. 2001 Nov 16;508(2):259-64. PMID:11718727
  2. ↑ Bowers S, Truong AP, Jeffrey Neitz R, Hom RK, Sealy JM, Probst GD, Quincy D, Peterson B, Chan W, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Lin M, Yao N, Artis DR, Zhang H, Chen L, Dryer M, Samant B, Zmolek W, Wong K, Lorentzen C, Goldbach E, Tonn G, Quinn KP, Sauer JM, Wright S, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I. Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100., Epub 2011 Jul 7. PMID:21813278 doi:http://dx.doi.org/10.1016/j.bmcl.2011.06.100

3rtp, resolution 2.40Å

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