8enj

From Proteopedia

(Difference between revisions)

Current revision

Design, synthesis, biological evaluation, and X-ray crystallography of diarylpyrazole derivatives possessing terminal arylsulfonamide moieties as anti-proliferative agents targeting c-Jun N-terminal kinase (JNK)

Structural highlights

8enj is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.81Å
Ligands:
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

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI(50s) and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI(50) of 1.28 muM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC(50) values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC(50) of 2.81 muM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC(50) of 4.82 muM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 degrees A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.

Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells.,Mersal KI, Abdel-Maksoud MS, Ali EMH, Ammar UM, Zaraei SO, Haque MM, Das T, Hassan NF, Kim EE, Lee JS, Park H, Lee KH, El-Gamal MI, Kim HK, Ibrahim TM, Oh CH Eur J Med Chem. 2023 Sep 15;261:115779. doi: 10.1016/j.ejmech.2023.115779. PMID:37776574^[2]

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

References

↑ 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
↑ Mersal KI, Abdel-Maksoud MS, Ali EMH, Ammar UM, Zaraei SO, Haque MM, Das T, Hassan NF, Kim EE, Lee JS, Park H, Lee KH, El-Gamal MI, Kim HK, Ibrahim TM, Oh CH. Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells. Eur J Med Chem. 2023 Sep 15;261:115779. PMID:37776574 doi:10.1016/j.ejmech.2023.115779

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8enj"

Categories: Homo sapiens | Large Structures | Mersal KI | Park H

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8enj is ON HOLD  until Paper Publication
+==Design, synthesis, biological evaluation, and X-ray crystallography of diarylpyrazole derivatives possessing terminal arylsulfonamide moieties as anti-proliferative agents targeting c-Jun N-terminal kinase (JNK)==
+<StructureSection load='8enj' size='340' side='right'caption='[[8enj]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8enj]] is a 1 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=8ENJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ENJ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.81&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WNK:N-[3-({(4P)-4-[(3M)-1-tert-butyl-3-(3-hydroxyphenyl)-1H-pyrazol-4-yl]pyridin-2-yl}amino)propyl]-4-hydroxybenzene-1-sulfonamide'>WNK</scene></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=8enj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8enj OCA], [https://pdbe.org/8enj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8enj RCSB], [https://www.ebi.ac.uk/pdbsum/8enj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8enj 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.
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI(50s) and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI(50) of 1.28 muM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC(50) values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC(50) of 2.81 muM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC(50) of 4.82 muM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 degrees A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.
-Authors: Park, H., Mersal, K.I.
+Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells.,Mersal KI, Abdel-Maksoud MS, Ali EMH, Ammar UM, Zaraei SO, Haque MM, Das T, Hassan NF, Kim EE, Lee JS, Park H, Lee KH, El-Gamal MI, Kim HK, Ibrahim TM, Oh CH Eur J Med Chem. 2023 Sep 15;261:115779. doi: 10.1016/j.ejmech.2023.115779. PMID:37776574<ref>PMID:37776574</ref>
-Description: Design, synthesis, biological evaluation, and X-ray crystallography of diarylpyrazole derivatives possessing terminal arylsulfonamide moieties as anti-proliferative agents targeting c-Jun N-terminal kinase (JNK)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Mersal, K.I]]
+<div class="pdbe-citations 8enj" style="background-color:#fffaf0;"></div>
-[[Category: Park, H]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Mersal KI]]
+[[Category: Park H]]

8enj

From Proteopedia

Current revision

Design, synthesis, biological evaluation, and X-ray crystallography of diarylpyrazole derivatives possessing terminal arylsulfonamide moieties as anti-proliferative agents targeting c-Jun N-terminal kinase (JNK)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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