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

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Lim JW,Kim SK,Choi SY,Kim DH,Gadhe CG,Lee HN,Kim HJ,Kim J,Cho SJ,Hwang H,Seong J,Jeong KS,Lee JY,Lim SM,Lee JW,Pae AN

doi

10.1016/j.ejmech.2018.07.071

subject

Has Abstract

pub_date

2018-09-05 00:00:00

pages

405-422

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30636-6

journal_volume

157

pub_type

杂志文章

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