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| - | {{STRUCTURE_3uli| PDB=3uli | SCENE= }}
| + | ==Human Cyclin Dependent Kinase 2 (CDK2) bound to azabenzimidazole derivative== |
| - | ===Human Cyclin Dependent Kinase 2 (CDK2) bound to azabenzimidazole derivative===
| + | <StructureSection load='3uli' size='340' side='right' caption='[[3uli]], [[Resolution|resolution]] 2.00Å' scene=''> |
| - | {{ABSTRACT_PUBMED_22305584}} | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[3uli]] 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=3ULI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ULI FirstGlance]. <br> |
| | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1N3:1-(AMINOMETHYL)-N-(3-{[6-BROMO-2-(4-METHOXYPHENYL)-3H-IMIDAZO[4,5-B]PYRIDIN-7-YL]AMINO}PROPYL)CYCLOPROPANECARBOXAMIDE'>1N3</scene></td></tr> |
| | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDK2, CDKN2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> |
| | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=3uli FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3uli OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3uli RCSB], [http://www.ebi.ac.uk/pdbsum/3uli PDBsum]</span></td></tr> |
| | + | </table> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKepsilon kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKepsilon. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKepsilon. |
| | | | |
| - | ==Function==
| + | Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKepsilon kinases.,Wang T, Block MA, Cowen S, Davies AM, Devereaux E, Gingipalli L, Johannes J, Larsen NA, Su Q, Tucker JA, Whitston D, Wu J, Zhang HJ, Zinda M, Chuaqui C Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018., Epub 2012 Jan 14. PMID:22305584<ref>PMID:22305584</ref> |
| - | [[http://www.uniprot.org/uniprot/CDK2_HUMAN CDK2_HUMAN]] Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization.<ref>PMID:10499802</ref> <ref>PMID:11051553</ref> <ref>PMID:10995386</ref> <ref>PMID:10995387</ref> <ref>PMID:10884347</ref> <ref>PMID:11113184</ref> <ref>PMID:15800615</ref> <ref>PMID:18372919</ref> <ref>PMID:20147522</ref> <ref>PMID:20079829</ref> <ref>PMID:20935635</ref> <ref>PMID:20195506</ref> <ref>PMID:19966300</ref> <ref>PMID:21262353</ref> <ref>PMID:21596315</ref> <ref>PMID:21319273</ref> <ref>PMID:17495531</ref>
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| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[3uli]] 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=3ULI OCA].
| + | </div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | <ref group="xtra">PMID:022305584</ref><references group="xtra"/><references/>
| + | *[[Cell division protein kinase 2|Cell division protein kinase 2]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Cyclin-dependent kinase]] | | [[Category: Cyclin-dependent kinase]] |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Larsen, N A.]] | + | [[Category: Larsen, N A]] |
| - | [[Category: Tucker, J A.]] | + | [[Category: Tucker, J A]] |
| - | [[Category: Wang, T.]] | + | [[Category: Wang, T]] |
| | [[Category: Azabenzimidazole derivative]] | | [[Category: Azabenzimidazole derivative]] |
| | [[Category: Complex with cyclin a or cyclin e]] | | [[Category: Complex with cyclin a or cyclin e]] |
| | [[Category: Phosphotransfer]] | | [[Category: Phosphotransfer]] |
| | [[Category: Transferase-transferase inhibitor complex]] | | [[Category: Transferase-transferase inhibitor complex]] |
| Structural highlights
Publication Abstract from PubMed
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKepsilon kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKepsilon. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKepsilon.
Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKepsilon kinases.,Wang T, Block MA, Cowen S, Davies AM, Devereaux E, Gingipalli L, Johannes J, Larsen NA, Su Q, Tucker JA, Whitston D, Wu J, Zhang HJ, Zinda M, Chuaqui C Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018., Epub 2012 Jan 14. PMID:22305584[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang T, Block MA, Cowen S, Davies AM, Devereaux E, Gingipalli L, Johannes J, Larsen NA, Su Q, Tucker JA, Whitston D, Wu J, Zhang HJ, Zinda M, Chuaqui C. Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKepsilon kinases. Bioorg Med Chem Lett. 2012 Mar 1;22(5):2063-9. doi: 10.1016/j.bmcl.2012.01.018., Epub 2012 Jan 14. PMID:22305584 doi:10.1016/j.bmcl.2012.01.018
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