6n9p
From Proteopedia
(Difference between revisions)
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==Discovery of affinity-based probes for Btk occupancy assay== | ==Discovery of affinity-based probes for Btk occupancy assay== | ||
| - | <StructureSection load='6n9p' size='340' side='right'caption='[[6n9p]]' scene=''> | + | <StructureSection load='6n9p' size='340' side='right'caption='[[6n9p]], [[Resolution|resolution]] 2.23Å' 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=6N9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N9P FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N9P 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=6n9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n9p OCA], [https://pdbe.org/6n9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n9p RCSB], [https://www.ebi.ac.uk/pdbsum/6n9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n9p 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]] 2.23Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KHD:N-(3-{[2-amino-3-(4-phenoxyphenyl)pyridin-4-yl]oxy}phenyl)propanamide'>KHD</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=6n9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n9p OCA], [https://pdbe.org/6n9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n9p RCSB], [https://www.ebi.ac.uk/pdbsum/6n9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n9p ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pe ntanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}p henyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. | ||
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| + | Discovery of Affinity-Based Probes for Btk Occupancy Assays.,Qiu H, Caldwell R, Liu-Bujalski L, Goutopoulos A, Jones R, Potnick J, Sherer B, Bender A, Grenningloh R, Xu D, Gardberg A, Mochalkin I, Johnson T, Viacava Follis A, Head J, Morandi F ChemMedChem. 2019 Jan 22;14(2):217-223. doi: 10.1002/cmdc.201800714. Epub 2019, Jan 9. PMID:30521698<ref>PMID:30521698</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6n9p" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Mochalkin I]] | [[Category: Mochalkin I]] | ||
Current revision
Discovery of affinity-based probes for Btk occupancy assay
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