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Eur J Med Chem. 2018 Sep 5;157:405-422. doi: 10.1016/j.ejmech.2018.07.071. Epub 2018 Aug 3.

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

Author information

1
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea.
2
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
3
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Department of Chemistry, Yonsei University, Seoul, 03722, Republic of Korea.
4
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
5
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, Republic of Korea.
6
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea.
7
Department of Chemistry, Yonsei University, Seoul, 03722, Republic of Korea.
8
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea; Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea. Electronic address: ljy@khu.ac.kr.
9
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science and Technology, Korea University of Science and Technology, Daejon, 34113, Republic of Korea. Electronic address: smlim28@kist.re.kr.
10
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; Division of Bio-Medical Science and Technology, Korea University of Science and Technology, Daejon, 34113, Republic of Korea. Electronic address: jwlee5@kist.re.kr.
11
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, 02447, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, 02792, Republic of Korea. Electronic address: anpae@kist.re.kr.

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.

KEYWORDS:

Alzheimer's disease; Crizotinib; SH2 domain-containing inositol 5′-phosphatase 2; Tau

PMID:
30103190
DOI:
10.1016/j.ejmech.2018.07.071
[Indexed for MEDLINE]

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