Discovery of new aminopyrimidine-based phosphoinositide 3-kinase beta (PI3Kβ) inhibitors with selectivity over PI3Kα.
Phosphatidylinositol-3-kinase beta (PI3Kβ) is an important therapeutic target in arterial thrombosis and special types of cancer. In this study, a new series of aminopyridine-based PI3Kβ selective inhibitors have been developed by the structure-based design strategy. When incorporated with the phenyl ring on sulfonamide moiety, aminopyrimidine analogs showed good potency on PI3Kβ and selectivity over PI3Kα. Intriguingly, replacement of phenyl group on sulfonamide with naphthyl group enhanced selectivity over PI3Kα while retaining submicromolar PI3Kβ potency. Molecular modeling suggests that increased PI3Kβ specificity is caused by the interaction with salt bridge (Lys782-Asp923) and Asp862 that creat a unique pocket in PI3Kβ. These results clearly provide useful insight in the design of new PI3Kβ inhibitors with high potency and selectivity.
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Jinhee
J
Kim
Seunghee
S
Hong
Sungwoo
S
Hong
D000631:Aminopyridines / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry* / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000187:drug effects; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011744:Pyrimidinones; C504718:TGX 221; D058539:Phosphatidylinositol 3-Kinase