Resistance mutations to imatinib and successor compounds BCR-Abl

Of the resistance mutations, these are believed to act by two mechanisms. Some of these mutations occur at inward-facing residues of the ATP binding site, which also binds the inhibitor. In this case, a significant decrease in inhibitor binding potency occurs, but the binding of ATP tolerates the mutated residue. The second effect of resistance mutations is to shift the equilibrium of the kinase to its active form. Since imatinib binds to the inactive form of the kinase, this will reduce the availability of its binding state. 

In addition to a direct effect on the shape and character of the binding pocket, recent mutagenesis suggests that gatekeeper mutations in several 

The final hinge motif interaction is G321W, which replaces a small, highly mobile residue with the largest aromatic residue. The resulting steric clash and change in kinase dynamics may combine to reduce the potency of imatinib to this mutated kinase. 

---