View source for 6vn5


==USP7 IN COMPLEX WITH LIGAND COMPOUND 7==
<StructureSection load='6vn5' size='340' side='right'caption='[[6vn5]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VN5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VN5 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]] 2.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R41:[(2R)-7-(2-aminopyridin-4-yl)-5-chloro-2,3-dihydro-1-benzofuran-2-yl](piperazin-1-yl)methanone'>R41</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=6vn5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vn5 OCA], [https://pdbe.org/6vn5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vn5 RCSB], [https://www.ebi.ac.uk/pdbsum/6vn5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vn5 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
USP7 is a promising target for cancer therapy as its inhibition is expected to decrease function of oncogenes, increase tumor suppressor function, and enhance immune function. Using a structure-based drug design strategy, a new class of reversible USP7 inhibitors has been identified that is highly potent in biochemical and cellular assays and extremely selective for USP7 over other deubiquitinases (DUBs). The succinimide was identified as a key potency-driving motif, forming two strong hydrogen-bonds to the allosteric pocket of USP7. Re-design of an initial benzofuran-amide scaffold yielded a simplified ether series of inhibitors, utilizing acyclic conformational control to achieve proper amine placement. Further improvements were realized upon replacing the ether-linked amines with carbon-linked morpholines, a modification motivated by Free Energy Perturbation (FEP+) calculations. This led to the discovery of compound 41, a highly potent, selective, and orally bioavailable USP7 inhibitor. In xenograft studies, compound 41 demonstrated tumor growth inhibition in both p53 wildtype and p53 mutant cancer cell lines, demonstrating that USP7 inhibitors can suppress tumor growth through multiple different pathways.

Discovery of Potent, Selective, and Orally Bioavailable Inhibitors of USP7 with In Vivo Anti-Tumor Activity.,Leger PR, Hu DX, Biannic B, Bui M, Han X, Karbarz E, Maung J, Okano A, Osipov M, Shibuya GM, Young K, Higgs C, Abraham B, Bradford D, Cho C, Colas C, Jacobson S, Ohol YM, Pookot D, Rana P, Sanchez J, Shah N, Sun M, Wong S, Brockstedt DG, Kassner PD, Schwarz JB, Wustrow DJ J Med Chem. 2020 Apr 17. doi: 10.1021/acs.jmedchem.0c00245. PMID:32302140<ref>PMID:32302140</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vn5" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thioesterase 3D structures|Thioesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Blaesse M]]
[[Category: Hu DX]]
[[Category: Krapp S]]
[[Category: Leger PR]]
[[Category: Maskos K]]
[[Category: Wustrow DJ]]