7dt2

Strategic design of catalytic lysine-targeting reversible covalent BCR-ABL Inhibitors

spinqualitylabelsall models 7dt2, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: HJ9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase 3D structures

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