Synergy and Antagonism between Allosteric and Active‐Site Inhibitors of Abl Tyrosine Kinase

Allosteric inhibitors of Abl kinase are being explored in the clinic, often in combination with ATP‐site inhibitors of Abl kinase. However, there are conflicting data on whether both ATP‐competitive inhibitors and myristoyl‐site allosteric inhibitors can simultaneously bind Abl kinase. Here, we determine whether there is synergy or antagonism between ATP‐competitive inhibitors and allosteric inhibitors of Abl. We observe that clinical ATP‐competitive inhibitors are not synergistic with allosteric ABL inhibitors, however, conformation‐selective ATP‐site inhibitors that modulate the global conformation of Abl can afford synergy. We demonstrate that kinase conformation is the key driver to simultaneously bind two compounds to Abl kinase. Finally, we explore the interaction of allosteric and conformation selective ATP‐competitive inhibitors in a series of biochemical and cellular assays. We describe a better understanding of the interaction between allosteric and ATP‐competitive inhibitors of Abl. Using a protease accessibility assay we developed, we determined the global conformation of Abl when bound to Abl inhibitors. We found that synergy between ATP‐competitive and allosteric inhibitors of Abl required a „matched“ kinase conformation.