7uc6
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7uc6]] 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=7UC6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UC6 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7uc6]] 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=7UC6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UC6 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MJ6:N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N~3~-(4-bromophenyl)-N,N-dimethyl-beta-alaninamide'>MJ6</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]] 3.101Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MJ6:N-{5-[difluoro(phosphono)methyl]-1-benzothiophene-2-carbonyl}-3-methyl-L-valyl-L-prolyl-N~3~-(4-bromophenyl)-N,N-dimethyl-beta-alaninamide'>MJ6</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=7uc6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uc6 OCA], [https://pdbe.org/7uc6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uc6 RCSB], [https://www.ebi.ac.uk/pdbsum/7uc6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uc6 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=7uc6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uc6 OCA], [https://pdbe.org/7uc6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uc6 RCSB], [https://www.ebi.ac.uk/pdbsum/7uc6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uc6 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules. | STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective STAT5 degrader with strong antitumor activity in vivo. We first obtained small-molecule ligands with sub-micromolar to low micromolar binding affinities to STAT5 and STAT6 SH2 domains and determined co-crystal structures of three such ligands in complex with STAT5A. We successfully transformed these ligands into potent and selective STAT5 degraders using the PROTAC technology with AK-2292 as the best compound. AK-2292 effectively induces degradation of STAT5A, STAT5B, and phosphorylated STAT5 proteins in a concentration- and time-dependent manner in acute myeloid leukemia (AML) cell lines and demonstrates excellent degradation selectivity for STAT5 over all other STAT members. It exerts potent and specific cell growth inhibitory activity in AML cell lines with high levels of phosphorylated STAT5. AK-2292 effectively reduces STAT5 protein in vivo and achieves strong antitumor activity in mice at well-tolerated dose schedules. | ||
| - | Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia.,Kaneshige A, Bai L, Wang M, McEachern D, Meagher JL, Xu R, Kirchhoff PD, Wen B, Sun D, Stuckey JA, Wang S J Med Chem. 2023 Feb | + | Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia.,Kaneshige A, Bai L, Wang M, McEachern D, Meagher JL, Xu R, Kirchhoff PD, Wen B, Sun D, Stuckey JA, Wang S J Med Chem. 2023 Feb 23;66(4):2717-2743. doi: 10.1021/acs.jmedchem.2c01665. Epub , 2023 Feb 3. PMID:36735833<ref>PMID:36735833</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
Stat5a Core in complex with Compound 12
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