123rd General Meeting of the KCS

Type Oral Presentation
Area Oral Presentation of Young Discovery Chemists
Room No. Room 304
Time THU 10:30-10:45
Code MEDI.O-7
Subject Identification of novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease
Authors Jiwoong Lim, Ae Nim Pae1,*, Sang Min Lim1, Jae Yeol Lee2, Jae Wook Lee3
Convergence Research Center for Diagnosis, Treatme, Korea Institute of Science and Technology, Korea
1Korea Institute of Science and Technology, Korea
2Department of Chemistry, Kyung Hee University, Korea
3Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
Abstract SH2 domain-containing inositol 5’-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in various human diseases including type 2 diabetes, cancer, and neurodegenerative diseases. A recent report demonstrated that inhibition of SHIP2 leads to functional restoration of the Akt/GSK3-dependent pathway by reducing the levels of PI(3,4)P2. Furthermore, the fact that downregulation of the SHIP2 reduced tau hyperphosphorylation induced by amyloid β and rescued the memory impairment in a Alzheimer’s disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer’s disease. In this study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of hit compounds discovered from a high-throughput screening. The biological evaluation revealed that some of the synthesized compounds had good potency on SHIP2 inhibition with reasonable drug-like properties in comparison with reference compounds. Notably, one of these derivatives, compound 43, showed promising properties in an in vivo pharmacokinetic evaluation and BBB penetration study. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor may function as a promising lead compound for the treatment of Alzheimer’s disease.
E-mail limjw123@naver.com