120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-297
Subject Design and Synthesis of the Novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease
Authors JIWOONG LIM, Seokkyu Kim1, Dong Hoi KIM2, Jae Wook Lee3, SANG MIN LIM4, Jae Yeol Lee1,*, Ae Nim Pae3,*
KHU-KIST Department of Converging Science and Tech, Kyung Hee University, Korea
1Department of Chemistry, Kyung Hee University, Korea
2Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
3Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
4Center for Neuromedicine, Korea Institute of Science and Technology, Korea
Abstract SHIP2, a lipid phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2, plays a pivotal role in regulating several intracellular signaling pathways and is involved in the pathogenesis of various diseases through its phosphatase activity and localization changes. Recent studies have suggested that inhibition of SHIP2 could produce a significant benefits in the treatment of Alzheimer’s Disease (AD). AD is characterized by amyloid-β (Aβ) plaques in the brain and neurofibrillary tangles of hyper-phosphorylated tau, a microtubule-binding protein. The 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 can be an effective therapeutic strategy in AD. For developing SHIP2 inhibitors, we performed the phosphatase assay with malachite green using in house libraries. From high-throughput screening, we found hit compounds, and synthesized new derivatives based on the hit scaffolds. Among the synthesized compounds, DTC0461 was identified as a potent SHIP2 inhibitor. The optimization of novel SHIP2 inhibitors to further enhance potency and physicochemical properties is now in progress. We have presented the first example of a small molecule SHIP2 inhibitors for AD. This compound will help to elucidate physiological functions of SHIP2 and its involvement in AD.
E-mail T16022@kist.re.kr