7qhl
From Proteopedia
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<table><tr><td colspan='2'>[[7qhl]] is a 4 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=7QHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QHL FirstGlance]. <br> | <table><tr><td colspan='2'>[[7qhl]] is a 4 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=7QHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QHL FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</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]] 1.7Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D5P:5-(2- | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D5P:5-(2-azanylethylsulfanyl)-3-cyclobutyl-~{N}-[(4-pyrazol-1-ylphenyl)methyl]-1~{H}-pyrazolo[4,3-d]pyrimidin-7-amine'>D5P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SGM:MONOTHIOGLYCEROL'>SGM</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=7qhl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qhl OCA], [https://pdbe.org/7qhl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qhl RCSB], [https://www.ebi.ac.uk/pdbsum/7qhl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qhl ProSAT]</span></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=7qhl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qhl OCA], [https://pdbe.org/7qhl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qhl RCSB], [https://www.ebi.ac.uk/pdbsum/7qhl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qhl ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| - | 3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H- | + | 3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 A resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation. |
| - | 3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.,Jorda R, Havlicek L, Perina M, Vojackova V, Pospisil T, Djukic S, Skerlova J, Gruz J, Renesova N, Klener P, Rezacova P, Strnad M, Krystof V J Med Chem. 2022 Jul 14;65(13):8881-8896. doi: 10.1021/acs.jmedchem.1c02184. Epub, 2022 Jun 24. PMID:35749742<ref>PMID:35749742</ref> | + | 3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.,Jorda R, Havlicek L, Perina M, Vojackova V, Pospisil T, Djukic S, Skerlova J, Gruz J, Renesova N, Klener P, Rezacova P, Strnad M, Krystof V J Med Chem. 2022 Jul 14;65(13):8881-8896. doi: 10.1021/acs.jmedchem.1c02184. Epub , 2022 Jun 24. PMID:35749742<ref>PMID:35749742</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal structure of Cyclin-dependent kinase 2/cyclin A in complex with 3,5,7-Substituted pyrazolo[4,3-d]pyrimidine inhibitor 24
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