Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

GNF-2 is a recently discovered, selective allosteric Bcr– Ablinhibitor. Solution NMR, X-ray crystallography, mutagenesisand hydrogen exchange mass spectrometry are now used to show that GNF-2 binds to the myristate- binding siteof Abl, leading to changes in the structural dynamicsof the ATP- binding site. The results show that the combination of allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.