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- Title
Correspondence on "Synergy and Antagonism between Allosteric and Active‐Site Inhibitors of Abl Tyrosine Kinase"**.
- Authors
Jahnke, Wolfgang; Paladini, Johannes; Habazettl, Judith M.; Wiget, Andrea; Loo, Alice; Cowan Jacob, Sandra W.; Grzesiek, Stephan; Manley, Paul W.
- Abstract
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.
- Subjects
PROTEIN-tyrosine kinase inhibitors; CHRONIC myeloid leukemia; ISOTHERMAL titration calorimetry; NUCLEAR magnetic resonance; ADENOSINE triphosphate
- Publication
Angewandte Chemie, 2022, Vol 134, Issue 46, p1
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.202117276