Correspondence on “Synergy and Antagonism between Allosteric and Active‐Site Inhibitors of Abl Tyrosine Kinase”**

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 doseresponse 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. Structural biology studies indicate that the cytosolicAbelson ABL1b and ABL2b tyrosine kinases are autoregulated by their myristoylated N-termini, which interact with a myristate-binding pocket in the catalytic SH1 domain, remote from the binding site of adenosine triphosphate (ATP), from which the phosphate group is transferred to