119th General Meeting of the KCS

Type Poster Presentation
Area 의약화학
Room No. 포스터발표장
Time 4월 20일 (목요일) 11:00~12:30
Code MEDI.P-434
Subject Synthesis and Biological Evaluation of the Novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease
Authors 임지웅, 배애님1,*, 이재열2, 이재욱3, 김동회4, 임상민5
경희대학교 KHU-KIST 융합과학기술학과, Korea
1한국과학기술연구원(KIST) 생체과학연구본부, Korea
2경희대학교 화학과, Korea
3한국과학기술연구원(KIST) 치매DTC융합연구단, Korea
4한국과학기술연구원 치매DTC연구단, Korea
5한국과학기술연구원(KIST) 뇌의약연구단, Korea
Abstract Inositol polyphosphate 5-phosphatase (SHIP2) is an important negative regulator of intracellular phosphatidylinositol phosphate, a key second messenger of various intracellular signaling pathways. Recent studies have suggested that inhibition of SHIP2 could produce a significant benefits in the treatment of Alzheimer’s Disease (AD). It 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 PIP2(3,4), 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, DTC0217 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 limjw123@naver.com