5f4n
From Proteopedia
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==Multi-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)== | ==Multi-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)== | ||
| - | <StructureSection load='5f4n' size='340' side='right' caption='[[5f4n]], [[Resolution|resolution]] 1.91Å' scene=''> | + | <StructureSection load='5f4n' size='340' side='right'caption='[[5f4n]], [[Resolution|resolution]] 1.91Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5f4n]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F4N OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5f4n]] 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=5F4N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F4N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5UY:METHYL+6-[(5-CYANOPYRAZIN-2-YL)AMINO]-4-[[(2~{R})-MORPHOLIN-2-YL]METHYLAMINO]PYRIDINE-3-CARBOXYLATE'>5UY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.91Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5UY:METHYL+6-[(5-CYANOPYRAZIN-2-YL)AMINO]-4-[[(2~{R})-MORPHOLIN-2-YL]METHYLAMINO]PYRIDINE-3-CARBOXYLATE'>5UY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5f4n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f4n OCA], [https://pdbe.org/5f4n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f4n RCSB], [https://www.ebi.ac.uk/pdbsum/5f4n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f4n ProSAT]</span></td></tr> |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/CHK1_HUMAN CHK1_HUMAN] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> |
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5f4n" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5f4n" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Aherne GW]] |
| - | [[Category: | + | [[Category: Box G]] |
| - | [[Category: | + | [[Category: Boxall KJ]] |
| - | [[Category: Brown | + | [[Category: Brown N]] |
| - | [[Category: Cheung | + | [[Category: Cheung KJ]] |
| - | [[Category: Collins | + | [[Category: Collins I]] |
| - | [[Category: Eccles | + | [[Category: De Haven Brandon AK]] |
| - | [[Category: Eve | + | [[Category: Eccles SA]] |
| - | [[Category: Garrett | + | [[Category: Eve PD]] |
| - | [[Category: Hayes | + | [[Category: Garrett MD]] |
| - | [[Category: Henley | + | [[Category: Hayes A]] |
| - | [[Category: Jamin | + | [[Category: Henley AT]] |
| - | [[Category: Lainchbury | + | [[Category: Jamin Y]] |
| - | [[Category: Leonard | + | [[Category: Lainchbury M]] |
| - | [[Category: Matthews | + | [[Category: Leonard P]] |
| - | [[Category: McHardy | + | [[Category: Matthews TP]] |
| - | + | [[Category: McHardy T]] | |
| - | [[Category: Osborne | + | [[Category: Osborne JD]] |
| - | [[Category: Proisy | + | [[Category: Proisy N]] |
| - | [[Category: Raynaud | + | [[Category: Raynaud FI]] |
| - | [[Category: Reader | + | [[Category: Reader JC]] |
| - | [[Category: Robinson | + | [[Category: Robinson SP]] |
| - | [[Category: Valenti | + | [[Category: Valenti MR]] |
| - | [[Category: Walton | + | [[Category: Walton MI]] |
| - | [[Category: Westwood | + | [[Category: Westwood IM]] |
| - | [[Category: | + | [[Category: Van Montfort R]] |
| - | + | ||
Current revision
Multi-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)
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Categories: Homo sapiens | Large Structures | Aherne GW | Box G | Boxall KJ | Brown N | Cheung KJ | Collins I | De Haven Brandon AK | Eccles SA | Eve PD | Garrett MD | Hayes A | Henley AT | Jamin Y | Lainchbury M | Leonard P | Matthews TP | McHardy T | Osborne JD | Proisy N | Raynaud FI | Reader JC | Robinson SP | Valenti MR | Walton MI | Westwood IM | Van Montfort R
