121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-623
Subject Synthesis of the Novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease
Authors Seokkyu Kim, Ae Nim Pae1,*, Jae Yeol Lee, SANG MIN LIM1, Jae Wook Lee2, JIWOONG LIM3
Department of Chemistry, Kyung Hee University, Korea
1Korea Institute of Science and Technology, Korea
2Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
3KHU-KIST Department of Converging Science and Tech, Kyung Hee University, Korea
Abstract Alzheimer’s diseases (AD) is a chronic neurodegenerative disease that is most common case of dementia. The hallmarks of Alzheimer’s diseases are the senile plaque which is composed of Amyloid beta (Aβ) peptide and neurofibrillary tangles (NFTs) consisted of mainly hyperphosphorylated tau protein in the brain. However, the pathological link between Aβ and tau remains unknown. Recent studies have suggested that inhibition of lipid phosphatase known as SH2 domain-containing inositol 5’-phosphatase 2 (SHIP2) rescued tau hyperphosphorylation and improved memory impairments. Furthermore, interaction between SHIP2 and FcgRIIb is critical in Aβ1-42 induced tau pathology. The binding of Aβ1-42 to FcgRIIb induces ITIM phosphorylation and SHIP2 is recruited to interact with FcgRIIb. SHIP2 increases Ptdins(3,4)P2 levels by dephosphorylation of 5-phosphate group from Ptdins(3,4,5)P3 resulting in Gsk3β activation followed tau hyperphosphorylation. Therefore, Inhibition of SHIP2 protein can be a potent therapeutic strategy for Aβ1-42 induced tau hyperphosphorylation pathology in AD. In order to discovery SHIP2 hit compounds, the phosphatase assay with malachite green carried out our in house and commercial compound libraries. The high-throughput screening produced, several hit compounds and we synthesized new derivatives based on the scaffolds of hit compounds. Consequently, we could find out some compounds with improved physicochemical properties. The optimization of novel SHIP2 inhibitor is now in progress and these compounds will be help to understand physicochemical functions of SHIP2 and pathological pathways of AD.
E-mail kim_sukgue@naver.com