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-324
Subject Discovery of Novel SHIP2 Inhibitors for the Treatment of Alzheimer’s Disease
Authors Seo Yoon Choi, Ae Nim Pae1,*, Kyu-Sung Jeong*, JIWOONG LIM2, Jae Wook Lee1, Dong Hoi KIM1, SANG MIN LIM3
Department of Chemistry, Yonsei University, Korea
1Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
2KHU-KIST Department of Converging Science and Tech, Kyung Hee University, Korea
3Center for Neuromedicine, Korea Institute of Science and Technology, Korea
Abstract Alzheimer’s disease (AD) is characterized by the progressive loss of memory and the neuronal degeneration. The pathological hallmarks of AD are the presence of senile plaques consisting of Aβ peptide and neurofibrillary tangles (NFT) formed by abnormally hyperphosphorylated tau. Recent studies showed that the src homology 2 (SH2) containing inositol 5-phosphatase 2 (SHIP2) is a key mediator in delivering the toxic signal of Aβ to tau by binding to the phosphorylated FcγRIIb. Also, reducing the activity or amount of SHIP2 in mice that present the symptoms of Alzheimer’s disease reduced the hyperphosphorylation of the tau protein in their neurons and restored their memory to normal levels. Here, we synthesized a series of novel SHIP2 inhibitors based on hit compounds from high-throughput screening and their inhibitory effects were verified in malachite green phosphate assay. Among them, DTC0310 exhibited potent inhibition effect. However, it was not favorable in terms of its pharmacokinetic profiles. To improve the activity and cell permeability, further modifications of the compound was examined. In the process of modification for better pharmacokinetic properties, DTC0441 showed favorable inhibition effect. With this promising assay result, measuring the drug-like properties of DTC0441 is on process. This compound may provide crucial insight into a SHIP2 inhibitor, which could be utilized as a therapeutic tool for the treatment of AD.
E-mail 116519@kist.re.kr