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==Crystal structure of a CDK6/Vcyclin complex with inhibitor bound== | ==Crystal structure of a CDK6/Vcyclin complex with inhibitor bound== | ||
<StructureSection load='4tth' size='340' side='right' caption='[[4tth]], [[Resolution|resolution]] 2.90Å' scene=''> | <StructureSection load='4tth' size='340' side='right'caption='[[4tth]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4tth]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4tth]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Herpesvirus_saimiri_(strain_11) Herpesvirus saimiri (strain 11)] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4p41 4p41]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TTH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TTH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=24V:9-CYCLOPENTYL-N-(5-PIPERAZIN-1-YLPYRIDIN-2-YL)PYRIDO[4,5]PYRROLO[1,2-D]PYRIMIDIN-2-AMINE'>24V</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=24V:9-CYCLOPENTYL-N-(5-PIPERAZIN-1-YLPYRIDIN-2-YL)PYRIDO[4,5]PYRROLO[1,2-D]PYRIMIDIN-2-AMINE'>24V</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=4tth FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tth OCA], [https://pdbe.org/4tth PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tth RCSB], [https://www.ebi.ac.uk/pdbsum/4tth PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tth ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/CGH2_SHV21 CGH2_SHV21] May be highly relevant to the process of cellular transformation and rapid T-cell proliferation effected by HVS during latent infections of T-cells in susceptible hosts. | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 18: | ||
</div> | </div> | ||
<div class="pdbe-citations 4tth" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4tth" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Piper DE]] | |||
[[Category: Piper | [[Category: Walker N]] | ||
[[Category: Walker | [[Category: Wang Z]] | ||
[[Category: Wang | |||
Revision as of 13:54, 15 March 2023
Crystal structure of a CDK6/Vcyclin complex with inhibitor boundCrystal structure of a CDK6/Vcyclin complex with inhibitor bound
Structural highlights
FunctionCGH2_SHV21 May be highly relevant to the process of cellular transformation and rapid T-cell proliferation effected by HVS during latent infections of T-cells in susceptible hosts. Publication Abstract from PubMedWe describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation. Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3.,Li Z, Wang X, Eksterowicz J, Gribble MW Jr, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, Degraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC J Med Chem. 2014 Apr 24;57(8):3430-49. doi: 10.1021/jm500118j. Epub 2014 Apr 2. PMID:24641103[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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