FIGURE 9.8. Interactions of ATP (A) and gefitinib (B) in the catalytic domain of EGFR.

between the different kinases, allowing relatively selective inhibitors, and is normally occupied by the above-discussed drugs, which thus act as ATP mimics. For instance, the interaction between gefitinib and the EGFR catalytic domain has been studied by X-ray crystallography15 and can be found in Fig. 9.8B. In the case of gefitinib, where the N-1 atom of the quinazoline ring acts as a hydrogen bond acceptor in an interaction with Met-769, the N-3 atom interacts with Thr-830 through a bridging water molecule, and the aniline ring occupies the normally empty hydrophobic pocket.

Since the ATP binding site is quite spacious, other orientations are possible for inhibitors, even belonging to the same structural class. The substitution of the Met-790 residue for Thr leads to resistance to gefitinib and erlotinib due to steric hindrance to binding of the inhibitor.16

ATP-competitive inhibitors need to prevail over the high endogenous concentrations of ATP. For this reason, ATP-competitive EGFR inhibitors are rapidly cleared from tumors. To overcome this problem, intensive efforts have been directed towards the development of irreversible EGFR inhibitors. Some of them are canertinib (CI-1003), a dual EGFR-HER-2 inhibitor,17 EKI-785, EKB-569, and HKI-272, which are under clinical evaluation.2,5 In some of these compounds, like EKB-569 and HKI-272, the traditional quinazoline ring has been replaced by a 3-cyanoquinoline.

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