8c78: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older edit
OCA (talk | contribs)
Bots, Bureaucrats, journal, Administrators
3,331,613 edits
No edit summary
OCA (talk | contribs)
Bots, Bureaucrats, journal, Administrators
3,331,613 edits
No edit summary
 
Line 4: Line 4:
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8c78]] is a 1 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=8C78 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8C78 FirstGlance]. <br>
<table><tr><td colspan='2'>[[8c78]] is a 1 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=8C78 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8C78 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TWI:(2~{S})-10-[(3-chloranyl-2-fluoranyl-pyridin-4-yl)amino]-2-cyclopropyl-3,3-bis(fluoranyl)-7-methyl-2,4-dihydro-1~{H}-[1,4]oxazepino[2,3-c]quinolin-6-one'>TWI</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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TWI:(2~{S})-10-[(3-chloranyl-2-fluoranyl-pyridin-4-yl)amino]-2-cyclopropyl-3,3-bis(fluoranyl)-7-methyl-2,4-dihydro-1~{H}-[1,4]oxazepino[2,3-c]quinolin-6-one'>TWI</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=8c78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c78 OCA], [https://pdbe.org/8c78 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c78 RCSB], [https://www.ebi.ac.uk/pdbsum/8c78 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c78 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=8c78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c78 OCA], [https://pdbe.org/8c78 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c78 RCSB], [https://www.ebi.ac.uk/pdbsum/8c78 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c78 ProSAT]</span></td></tr>
</table>
</table>
Line 11: Line 12:
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.<ref>PMID:9649500</ref> <ref>PMID:18280243</ref>  
[https://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.<ref>PMID:9649500</ref> <ref>PMID:18280243</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.
Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones.,Harnden AC, Davis OA, Box GM, Hayes A, Johnson LD, Henley AT, de Haven Brandon AK, Valenti M, Cheung KJ, Brennan A, Huckvale R, Pierrat OA, Talbot R, Bright MD, Akpinar HA, Miller DSJ, Tarantino D, Gowan S, de Klerk S, McAndrew PC, Le Bihan YV, Meniconi M, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Bellenie BR, Hoelder S J Med Chem. 2023 Apr 7. doi: 10.1021/acs.jmedchem.3c00155. PMID:37026591<ref>PMID:37026591</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8c78" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
Retrieved from "https://proteopedia.org/8c78"