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

Citations Over TimeTop 10% of 1999 papers

Abstract

4-Anilinoquinazolines represent an important class of protein kinase inhibitor. Modes of binding for two members of this inhibitor class were determined 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 complex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoquinazoline was bound in the ATP site with the quinazoline ring system oriented along the peptide strand that links the two domains of the protein and with the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoline 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 interacted with backbone carbonyl oxygen atoms of the peptide strand. The anilino group of the CDK2-bound compound was essentially coplanar with the quinazoline 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.

Related Papers

• → 3D-QSAR CoMFA study on indenopyrazole derivatives as cyclin dependent kinase 4 (CDK4) and cyclin dependent kinase 2 (CDK2) inhibitors(2006)45 cited
• → Reciprocal Activation by Cyclin-Dependent Kinases 2 and 7 Is Directed by Substrate Specificity Determinants outside the T Loop(2001)70 cited
• p21 contains independent binding sites for cyclin and cdk2: both sites are required to inhibit cdk2 kinase activity.(1996)
• → Dual Cyclin-Binding Domains Are Required for p107 To Function as a Kinase Inhibitor(1998)68 cited
• → The N-Terminal Domains of Cyclin-Dependent Kinase Inhibitory Proteins Block the Phosphorylation of cdk2/Cyclin E by the CDK-Activating Kinase(2000)30 cited