Mixed Haloalkoxy Groups

In 2021, the FDA approved asciminib (ABL001), an allosteric inhibitor of the Philadelphia tyrosine kinase, which plays a key role in leukemia development. The drug features a chlorodifluoromethoxy- (ClF₂CO-) moiety, which embeds deeply within the myristate pocket. This group replaces the more commonly used CF₃O- moiety, doubling the binding affinity by forming a Cl∙∙∙O=C halogen bond with the backbone of Leu448. Interestingly, the transition from CF₃O- to ClF₂CO- did not increase lipophilicity. This example underscores the potential of mixed halogenated moieties for fine-tuning pocket interactions and optimizing drug pharmacology.