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6ckx

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Current revision

Structure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide

Structural highlights

6ckx is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Gene:	CDK12, CRK7, CRKRS, KIAA0904 (HUMAN), CCNK, CPR4 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CDK12_HUMAN] Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.

Function

[CDK12_HUMAN] Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors.^[1] ^[2] ^[3] [CCNK_HUMAN] May play a role in transcriptional regulation. In vitro, is associated with a kinase activity toward both RNA polymerase II C-terminal domain and CDK2 (CAK).^[4]

Publication Abstract from PubMed

Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors. Structure-activity relationship studies of a HTS hit, structure-based drug design, and conformation-oriented design using the Cambridge Structural Database afforded the optimized compound 2, which exhibited not only potent CDK12 (and CDK13) inhibitory activity and excellent selectivity but also good physicochemical properties. Furthermore, 2 inhibited the phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and induced growth inhibition in SK-BR-3 cells. Therefore, 2 represents an excellent chemical probe for functional studies of CDK12 and could be a promising lead compound for drug discovery.

Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors.,Ito M, Tanaka T, Toita A, Uchiyama N, Kokubo H, Morishita N, Klein MG, Zou H, Murakami M, Kondo M, Sameshima T, Araki S, Endo S, Kawamoto T, Morin GB, Aparicio SA, Nakanishi A, Maezaki H, Imaeda Y J Med Chem. 2018 Aug 20. doi: 10.1021/acs.jmedchem.8b00683. PMID:30067358^[5]

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

References

↑ Ko TK, Kelly E, Pines J. CrkRS: a novel conserved Cdc2-related protein kinase that colocalises with SC35 speckles. J Cell Sci. 2001 Jul;114(Pt 14):2591-603. PMID:11683387
↑ Iorns E, Martens-de Kemp SR, Lord CJ, Ashworth A. CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. Carcinogenesis. 2009 Oct;30(10):1696-701. doi: 10.1093/carcin/bgp187. Epub 2009, Aug 3. PMID:19651820 doi:http://dx.doi.org/10.1093/carcin/bgp187
↑ Bartkowiak B, Liu P, Phatnani HP, Fuda NJ, Cooper JJ, Price DH, Adelman K, Lis JT, Greenleaf AL. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010 Oct 15;24(20):2303-16. doi: 10.1101/gad.1968210. PMID:20952539 doi:http://dx.doi.org/10.1101/gad.1968210
↑ Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem. 1999 Dec 3;274(49):34527-30. PMID:10574912
↑ Ito M, Tanaka T, Toita A, Uchiyama N, Kokubo H, Morishita N, Klein MG, Zou H, Murakami M, Kondo M, Sameshima T, Araki S, Endo S, Kawamoto T, Morin GB, Aparicio SA, Nakanishi A, Maezaki H, Imaeda Y. Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors. J Med Chem. 2018 Aug 20. doi: 10.1021/acs.jmedchem.8b00683. PMID:30067358 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00683

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/6ckx"

@@ Line 3: / Line 3: @@
 <StructureSection load='6ckx' size='340' side='right' caption='[[6ckx]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ckx]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CKX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CKX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ckx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CKX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CKX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8M1:N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-{trans-4-[(quinazolin-2-yl)amino]cyclohexyl}acetamide'>8M1</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CDK12, CRK7, CRKRS, KIAA0904 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CCNK, CPR4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ckx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ckx OCA], [http://pdbe.org/6ckx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ckx RCSB], [http://www.ebi.ac.uk/pdbsum/6ckx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ckx ProSAT]</span></td></tr>
 </table>
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Klein, M G]]
 [[Category: Inhibitor]]

6ckx

From Proteopedia

Current revision

Structure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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