This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

3ptg

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

Design and Synthesis of a Novel, Orally Efficacious Tri-substituted Thiophene Based JNK Inhibitor

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ptg"

@@ Line 3: / Line 3: @@
 <StructureSection load='3ptg' size='340' side='right'caption='[[3ptg]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ptg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PTG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PTG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ptg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PTG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PTG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=932:N-[4-METHYL-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>932</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.43&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK10, JNK3, JNK3A, PRKM10 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=932:N-[4-METHYL-3-(1H-1,2,4-TRIAZOL-5-YL)THIOPHEN-2-YL]-2-(2-OXO-3,4-DIHYDROQUINOLIN-1(2H)-YL)ACETAMIDE'>932</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3ptg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ptg OCA], [https://pdbe.org/3ptg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ptg RCSB], [https://www.ebi.ac.uk/pdbsum/3ptg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ptg ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[https://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. [[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN]] Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:10700186</ref>
+[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN] Defects in MAPK8IP1 are a cause of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:[https://omim.org/entry/125853 125853]. NIDDM is characterized by an autosomal dominant mode of inheritance, onset during adulthood and insulin resistance.<ref>PMID:10700186</ref>
 == Function ==
-[[https://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>  [[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN]] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
+[https://www.uniprot.org/uniprot/JIP1_HUMAN JIP1_HUMAN] The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module. Required for JNK activation in response to excitotoxic stress. Cytoplasmic MAPK8IP1 causes inhibition of JNK-regulated activity by retaining JNK in the cytoplasm and inhibiting JNK phosphorylation of c-Jun. May also participate in ApoER2-specific reelin signaling. Directly, or indirectly, regulates GLUT2 gene expression and beta-cell function. Appears to have a role in cell signaling in mature and developing nerve terminals. May function as a regulator of vesicle transport, through interactions with the JNK-signaling components and motor proteins (By similarity). Functions as an anti-apoptotic protein and whose level seems to influence the beta-cell death or survival response.
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
-Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor.,Bowers S, Truong AP, Neitz RJ, Neitzel M, Probst GD, Hom RK, Peterson B, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Yao N, Artis DR, Brigham EF, Quinn KP, Sauer JM, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2011 Jan 20. PMID:21316234<ref>PMID:21316234</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 3ptg" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 29: / Line 19: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Mitogen-activated protein kinase]]
+[[Category: Artis DR]]
-[[Category: Artis, D R]]
+[[Category: Bard F]]
-[[Category: Bard, F]]
+[[Category: Bowers S]]
-[[Category: Bowers, S]]
+[[Category: Brigham EF]]
-[[Category: Brigham, E F]]
+[[Category: Griswold-Prenner I]]
-[[Category: Griswold-Prenner, I]]
+[[Category: Hom RK]]
-[[Category: Hom, R K]]
+[[Category: Konradi AW]]
-[[Category: Konradi, A W]]
+[[Category: Neitz J]]
-[[Category: Neitz, J]]
+[[Category: Neitzel M]]
-[[Category: Neitzel, M]]
+[[Category: Pan H]]
-[[Category: Pan, H]]
+[[Category: Powell K]]
-[[Category: Powell, K]]
+[[Category: Probst GD]]
-[[Category: Probst, G D]]
+[[Category: Quinn KP]]
-[[Category: Quinn, K P]]
+[[Category: Ruslim L]]
-[[Category: Ruslim, L]]
+[[Category: Sauer J]]
-[[Category: Sauer, J]]
+[[Category: Sham HL]]
-[[Category: Sham, H L]]
+[[Category: Toth G]]
-[[Category: Toth, G]]
+[[Category: Truong AP]]
-[[Category: Truong, A P]]
+[[Category: Yao N]]
-[[Category: Yao, N]]
+[[Category: Yednock TA]]
-[[Category: Yednock, T A]]
-[[Category: Jnk inhibitor]]
-[[Category: Neurodegeneration]]
-[[Category: Thiophene]]
-[[Category: Transferase-transferase inhibitor complex]]

3ptg

From Proteopedia

Current revision

Design and Synthesis of a Novel, Orally Efficacious Tri-substituted Thiophene Based JNK Inhibitor

Structural highlights

Disease

Function

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox