Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease
- Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease
- 배애님; 이재욱; 성지혜; 임상민; 가디 장데부 고라크스나트; 이해님; 김동회; 임지웅; 최서윤; 김석규; 김효지; 김진아; 조성진; 황하영; 정규성; 이재열
- Issue Date
- European journal of medicinal chemistry
- VOL 157-422
- SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid β and rescued memory impairment in a transgenic Alzheimer's disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer's disease. In the present study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Our representative compound 43 potently inhibited SHIP2 activity as well as GSK3β activation in HT22 neuronal cells. It was also shown that 43 has favorable physicochemical properties, especially high brain penetration. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor 43 may function as a promising lead compound for the treatment of Alzheimer's disease.
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