Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase

4-Anilinoquinazolines represent an important class of protein kinase inhibi tor. Modes of binding for two members of this inhibitor class were determin ed by X-ray crystallographic analysis of one inhibitor(4-[3-hydroxyanilino] -6,7-dimethoxyquinazoline)in complex with cyclin-dependent kinase 2 (CDK2) and the other (4-[3-methylsulfanylanilino]-6,7-dimethoxyquinazoline) in com plex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoqui nazoline was bound in the ATP site with the quinazoline ring system oriente d along the peptide strand that links the two domains of the protein and wi th the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoli ne accepted a hydrogen bond from a backbone NH (CDK2, Leu-83; p38, Met-109) of the domain connector strand, and aromatic hydrogen atoms at C2 and C8 i nteracted with backbone carbonyl oxygen atoms of the peptide strand. The an ilino group of the CDK2-bound compound was essentially coplanar with the qu inazoline ring system and occupied a pocket between Lys-33 and Phe-80. For the p38-bound inhibitor, the anilino group was angled out of plane and was positioned between Lys-53 and Thr-106 in a manner similar to that observed for the aryl substituent of the pyridinylimidazole class of inhibitor.