Identification of lead small molecule inhibitors of glycogen synthase kinase-3 beta using a fragment-linking strategy.
Glycogen synthase kinase-3 beta (GSK3β) kinase serves as a promising therapeutic target for the treatment of various human diseases, such as diabetes, obesity, and Alzheimer's disease. In this study, we report lead GSK3β inhibitors identified using a fragment-linking strategy. Through the systematic exploration, a six-atom chain unit bearing the rigid double bond was found to be a suitable linker connecting two fragments, which enables favorable contacts with backbone groups of residues in the pockets. As a consequence, potent GSK3β inhibitor 9i was found with IC50values of 19nM. The binding mode analysis indicates that the activities of the inhibitors appear to be achieved by the establishment of multiple hydrogen bonds and hydrophobic interactions in the ATP-binding site of GSK3β. The good biochemical potencies and structural uniqueness of the inhibitors support consideration in the further study to optimize the biological activity.
Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 305-701, Republic of Korea.
Jinhee
J
Kim
Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 305-701, Republic of Korea; Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Yonghoon
Y
Moon
Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS), Daejeon 305-701, Republic of Korea; Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: hongorg@kaist.ac.kr.
Sungwoo
S
Hong
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
C023422:7-azaindole dimer; D004791:Enzyme Inhibitors; D007211:Indoles; D054852:Small Molecule Libraries; D000071679:Glycogen Synthase Kinase 3 beta
7-Azaindole; Fragment-linking strategy; Glycogen synthase kinase-3 beta; Inhibitor; Kinase