Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI 48109, USA.
Angew Chem Int Ed Engl. 2022 Nov 14;61(46):e202209518. doi: 10.1002/anie.202209518. Epub 2022 Oct 25.
Manley and co-workers provide data demonstrating that, at super-pharmacological concentrations (300 μM), a ternary complex between Abl, asciminib, and ATP-competitive inhibitors is possible. The work in our manuscript concerns the interplay of asciminib (and GNF-2) with ATP-competitive inhibitors at pharmacologically relevant concentrations (C =1.6-3.7 μM for asciminib). Manley and co-workers do not question any of the studies that we reported, nor do they provide explanations for how our work fits into their preferred model. Herein, we consider the data presented by Manley and co-workers. In addition, we provide new data supporting the findings in our Communication. Asciminib and ATP-competitive inhibitors do not simultaneously bind Abl at pharmacologically relevant concentrations unless the conformation selectivity for both ligands is matched.
曼利等人提供的数据表明，在超药理学浓度（300μM）下，Abl、asciminib 和 ATP 竞争抑制剂的三元复合物是可能的。我们的手稿中的工作涉及 asciminib（和 GNF-2）与在药理学相关浓度（asciminib 为 1.6-3.7μM）下的 ATP 竞争抑制剂的相互作用。曼利等人并没有质疑我们报告的任何研究，也没有解释我们的工作如何符合他们首选的模型。在此，我们考虑了曼利等人提供的数据。此外，我们还提供了新的数据来支持我们通讯中的发现。在药理学相关浓度下，asciminib 和 ATP 竞争抑制剂不会同时结合 Abl，除非两个配体的构象选择性相匹配。
