7run
From Proteopedia
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==Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor.== | ==Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor.== | ||
| - | <StructureSection load='7run' size='340' side='right'caption='[[7run]]' scene=''> | + | <StructureSection load='7run' size='340' side='right'caption='[[7run]], [[Resolution|resolution]] 3.51Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RUN FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RUN FirstGlance]. <br> | ||
| - | </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=7run FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7run OCA], [https://pdbe.org/7run PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7run RCSB], [https://www.ebi.ac.uk/pdbsum/7run PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7run ProSAT]</span></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]] 3.51Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QU:1-(4-{(1s,3s)-3-[4-amino-5-(3-amino-4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl}piperazin-1-yl)ethan-1-one'>7QU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=7run FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7run OCA], [https://pdbe.org/7run PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7run RCSB], [https://www.ebi.ac.uk/pdbsum/7run PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7run ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively. | ||
| + | |||
| + | Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.,Mathison CJN, Yang Y, Nelson J, Huang Z, Jiang J, Chianelli D, Rucker PV, Roland J, Xie YF, Epple R, Bursulaya B, Lee C, Gao MY, Shaffer J, Briones S, Sarkisova Y, Galkin A, Li L, Li N, Li C, Hua S, Kasibhatla S, Kinyamu-Akunda J, Kikkawa R, Molteni V, Tellew JE ACS Med Chem Lett. 2021 Nov 6;12(12):1912-1919. doi:, 10.1021/acsmedchemlett.1c00450. eCollection 2021 Dec 9. PMID:34917254<ref>PMID:34917254</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7run" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Tyrosine kinase receptor 3D structures|Tyrosine kinase receptor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor.
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