Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease

Title
Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease
Authors
배애님이재욱성지혜임상민가디 장데부 고라크스나트이해님김동회임지웅최서윤김석규김효지김진아조성진황하영정규성이재열
Issue Date
2018-09
Publisher
European journal of medicinal chemistry
Citation
VOL 157-422
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/68223
ISSN
0223-5234
Appears in Collections:
KIST Publication > Article
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE