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Synergy and Antagonism between Allosteric and Active‐Site Inhibitors of Abl Tyrosine Kinase
Author(s) -
Johnson Taylor K.,
Bochar Daniel A.,
Vandecan Nathalie M.,
Furtado Jessica,
Agius Michael P.,
Phadke Sameer,
Soellner Matthew B.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202105351
Subject(s) - allosteric regulation , chemistry , tyrosine kinase , allosteric enzyme , kinase , abl , biochemistry , antagonism , enzyme , signal transduction , receptor
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.