6udt: Difference between revisions

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<StructureSection load='6udt' size='340' side='right'caption='[[6udt]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
<StructureSection load='6udt' size='340' side='right'caption='[[6udt]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6udt]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UDT FirstGlance]. <br>
<table><tr><td colspan='2'>[[6udt]] 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=6UDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UDT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q4V:(4S,7aR,9aR,10S,11E,18R)-6-chloro-10,18-dihydroxy-15-methyl-16-oxo-3,4,7,7a,8,9,9a,10,13,14,15,16,17,18-tetradecahydro-2H,3H,5H-spiro[1,19-(ethanediylidene)cyclobuta[n][1,4]oxazepino[4,3-a][1,8]diazacyclohexadecine-4,1-naphthalene]-18-carboxylic+acid'>Q4V</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]] 1.5&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6ud2|6ud2]], [[6udi|6udi]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q4V:(4S,7aR,9aR,10S,11E,18R)-6-chloro-10,18-dihydroxy-15-methyl-16-oxo-3,4,7,7a,8,9,9a,10,13,14,15,16,17,18-tetradecahydro-2H,3H,5H-spiro[1,19-(ethanediylidene)cyclobuta[n][1,4]oxazepino[4,3-a][1,8]diazacyclohexadecine-4,1-naphthalene]-18-carboxylic+acid'>Q4V</scene></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=6udt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6udt OCA], [http://pdbe.org/6udt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6udt RCSB], [http://www.ebi.ac.uk/pdbsum/6udt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6udt 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=6udt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6udt OCA], [https://pdbe.org/6udt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6udt RCSB], [https://www.ebi.ac.uk/pdbsum/6udt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6udt ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an alpha-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.


Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an alpha-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.,Rescourio G, Gonzalez AZ, Jabri S, Belmontes B, Moody G, Whittington D, Huang X, Caenepeel S, Cardozo M, Cheng AC, Chow D, Dou H, Jones A, Kelly RC, Li Y, Lizarzaburu M, Lo MC, Mallari R, Meleza C, Rew Y, Simonovich S, Sun D, Turcotte S, Yan X, Wong SG, Yanez E, Zancanella M, Houze J, Medina JC, Hughes PE, Brown SP J Med Chem. 2019 Nov 27;62(22):10258-10271. doi: 10.1021/acs.jmedchem.9b01310., Epub 2019 Nov 18. PMID:31736296<ref>PMID:31736296</ref>
==See Also==
 
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6udt" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Huang, X]]
[[Category: Huang X]]
[[Category: Whittington, D]]
[[Category: Whittington D]]
[[Category: Apoptosis]]
[[Category: Apoptosis-inhibitor complex]]
[[Category: Inhibitor]]
[[Category: Protein-protein interaction]]

Latest revision as of 14:56, 13 March 2024

X-ray co-crystal structure of compound 10 bound to human Mcl-1

6udt, resolution 1.50Å

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