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4y46

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Revision as of 01:58, 10 March 2017

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors

Structural highlights

4y46 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4y5h
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

A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 muM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 A. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.,Zheng K, Park CM, Iqbal S, Hernandez P, Park H, LoGrasso PV, Feng Y ACS Med Chem Lett. 2015 Mar 2;6(4):413-8. doi: 10.1021/ml500474d. eCollection, 2015 Apr 9. PMID:25893042^[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
↑ Zheng K, Park CM, Iqbal S, Hernandez P, Park H, LoGrasso PV, Feng Y. Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors. ACS Med Chem Lett. 2015 Mar 2;6(4):413-8. doi: 10.1021/ml500474d. eCollection, 2015 Apr 9. PMID:25893042 doi:http://dx.doi.org/10.1021/ml500474d

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/4y46"

Categories: Mitogen-activated protein kinase | Park, H | Jnk | Map kinase | Transferase-transferase inhibitor complex

@@ Line 1: / Line 1: @@
 ==Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors==
 <StructureSection load='4y46' size='340' side='right' caption='[[4y46]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4y5h|4y5h]]</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=4y46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y46 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4y46 RCSB], [http://www.ebi.ac.uk/pdbsum/4y46 PDBsum]</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=4y46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y46 OCA], [http://pdbe.org/4y46 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y46 RCSB], [http://www.ebi.ac.uk/pdbsum/4y46 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y46 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4y46" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4y46

From Proteopedia

Revision as of 01:58, 10 March 2017

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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