Correspondence on "Synergy and Antagonism between Allosteric and Active-Site Inhibitors of Abl Tyrosine Kinase"

Jahnke, Wolfgang and Paladini, Johannes and Habazettl, Judith M. and Wiget, Andrea and Loo, Alice and Cowan Jacob, Sandra W. and Grzesiek, Stephan and Manley, Paul W.. (2022) Correspondence on "Synergy and Antagonism between Allosteric and Active-Site Inhibitors of Abl Tyrosine Kinase". Angewandte Chemie International Edition, 61 (46). e202117276.

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Soellner published on the interplay between allosteric and adenosine triphosphate (ATP)-competitive inhibitors of ABL kinase, showing that the latter preferably binds to different conformational states of ABL compared to allosteric agents that specifically target the ABL myristate pocket (STAMP) and deducing that asciminib cannot bind to ABL simultaneously with ATP-competitive drugs. These results are to some extent in line with ours, although our analyses of dose-response matrices from combinations of asciminib with imatinib, nilotinib or dasatinib, show neither synergy nor antagonism, but suggest additive antiproliferative effects on BCR-ABL-dependent KCL22 cells. Furthermore, our X-ray crystallographic, solution nuclear magnetic resonance (NMR), and isothermal titration calorimetry studies show that asciminib can bind ABL concomitantly with type-1 or -2 ATP-competitive inhibitors to form ternary complexes. Concomitant binding of asciminib with imatinib, nilotinib, or dasatinib might translate to benefit some chronic myeloid leukaemia patients.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan and Habazettl, Judith Maria and Paladini, Johannes
Item Type:Article
Article Subtype:Further Journal Contribution
Note:Publication type according to Uni Basel Research Database: Journal item
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Last Modified:19 Dec 2022 11:28
Deposited On:14 Dec 2022 10:19

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