View source for 7cc2


==Strategic design of catalytic lysine-targeting reversible covalent BCR-ABL Inhibitors==
<StructureSection load='7cc2' size='340' side='right'caption='[[7cc2]], [[Resolution|resolution]] 2.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CC2 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]] 2.723&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FVC:[4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-phenyl]boronic+acid'>FVC</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=7cc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cc2 OCA], [https://pdbe.org/7cc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cc2 RCSB], [https://www.ebi.ac.uk/pdbsum/7cc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cc2 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.

Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors.,Quach D, Tang G, Anantharajan J, Baburajendran N, Poulsen A, Wee J, Retna P, Li R, Liu B, Tee D, Kwek P, Joy J, Yang WQ, Zhang CJ, Foo K, Keller T, Yao SQ Angew Chem Int Ed Engl. 2021 May 19. doi: 10.1002/anie.202105383. PMID:34008286<ref>PMID:34008286</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7cc2" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Anantharajan J]]
[[Category: Baburajendran N]]