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| | ==CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone== | | ==CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone== |
| - | <StructureSection load='5idn' size='340' side='right' caption='[[5idn]], [[Resolution|resolution]] 2.26Å' scene=''> | + | <StructureSection load='5idn' size='340' side='right'caption='[[5idn]], [[Resolution|resolution]] 2.26Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5idn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IDN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IDN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5idn]] 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=5IDN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IDN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</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]] 2.26Å</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [http://pdbe.org/5idn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [http://www.ebi.ac.uk/pdbsum/5idn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [https://pdbe.org/5idn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [https://www.ebi.ac.uk/pdbsum/5idn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CDK8_HUMAN CDK8_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.<ref>PMID:10993082</ref> <ref>PMID:15546612</ref> [[http://www.uniprot.org/uniprot/CCNC_HUMAN CCNC_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.<ref>PMID:8700522</ref> <ref>PMID:16595664</ref> | + | [https://www.uniprot.org/uniprot/CDK8_HUMAN CDK8_HUMAN] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.<ref>PMID:10993082</ref> <ref>PMID:15546612</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 5idn" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5idn" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cyclin 3D structures|Cyclin 3D structures]] |
| | + | *[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Blagg, J]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Czodrowski, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Mallinger, A]] | + | [[Category: Blagg J]] |
| - | [[Category: Musil, D]] | + | [[Category: Czodrowski P]] |
| - | [[Category: Schiemann, K]] | + | [[Category: Mallinger A]] |
| - | [[Category: Cdk8 kinase / cyclin c]] | + | [[Category: Musil D]] |
| - | [[Category: Transferase]] | + | [[Category: Schiemann K]] |
| Structural highlights
Function
CDK8_HUMAN Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.[1] [2]
Publication Abstract from PubMed
The mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.
Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.,Czodrowski P, Mallinger A, Wienke D, Esdar C, Poschke O, Busch M, Rohdich F, Eccles SA, Ortiz-Ruiz MJ, Schneider R, Raynaud FI, Clarke PA, Musil D, Schwarz D, Dale T, Urbahns K, Blagg J, Schiemann K J Med Chem. 2016 Oct 27;59(20):9337-9349. Epub 2016 Oct 7. PMID:27490956[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Akoulitchev S, Chuikov S, Reinberg D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature. 2000 Sep 7;407(6800):102-6. PMID:10993082 doi:10.1038/35024111
- ↑ Fryer CJ, White JB, Jones KA. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell. 2004 Nov 19;16(4):509-20. PMID:15546612 doi:S1097276504006409
- ↑ Czodrowski P, Mallinger A, Wienke D, Esdar C, Poschke O, Busch M, Rohdich F, Eccles SA, Ortiz-Ruiz MJ, Schneider R, Raynaud FI, Clarke PA, Musil D, Schwarz D, Dale T, Urbahns K, Blagg J, Schiemann K. Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening. J Med Chem. 2016 Oct 27;59(20):9337-9349. Epub 2016 Oct 7. PMID:27490956 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00597
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