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제125회 대한화학회 학술발표회 및 총회 Synthesis and Biological Evaluation of the Novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease

2020년 2월 6일 14시 46분 37초
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Medicinal Chemistry
저자 및
Boeun Gu, Jae Wook Lee1, Sang Min Lim2, Yong sup Lee3, Ae Nim Pae4,*
Department of Pharmacy, Kyung Hee University, Korea
1Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
2Convergence Research Center for Diagnosis, Korea Institute of Science and Technology, Korea
3Department of Pharmacy, Kyung Hee University, Korea
4Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea
SH2 domain-containing inositol 5’-phosphatase 2 (SHIP2) is a lipid phosphatase that catalyses dephosphorylation 5-position of phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) to generate phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), and is involved in various human diseases including type 2 diabetes, cancer, and neurodegenerative diseases.1 A recent studies showed that SHIP2 is a key mediator in delivering the toxic signal of Aβ to tau by binding to the phosphorylated FcγRIIb. AD is characterized by amyloid-β (Aβ) plaques in the brain and neurofibrillary tangles of hyper-phosphorylated tau, a microtubule-binding protein. FcgRIIb-SHIP2 signaling axis could provide the missing link between Aβ and tau pathologies. Notably, Aβ1-42 induces FcgRIIb phosphorylation to recruit SHIP2, followed by increased production of PI(3,4)P2, disrupting the balance of phosphoinositide metabolism leading to tau hyperphosphorylation and memory impairment in neurons. Therefore, Inhibition of SHIP2 protein can be a potent therapeutic strategy for Aβ1-42 induced-tau hyperphosphorylation pathology in AD.2,3 In preceding reasearch, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Notably, one of these derivatives, showed promising properties in an in vivo pharmacokinetic evaluation and BBB penetration study.4 The optimization of novel SHIP2 inhibitors to further enhance potency and physicochemical properties is now in progress. Considering the fact that 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.