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

Ji Woong Lim, Seok Kyu Kim, Seo Yun Choi, Dong Hoi Kim, Changdev G. Gadhe, Hae Nim Lee, Hyo Ji Kim, Jina Kim, Sung Jin Cho, Hayoung Hwang, Jihye Seong, Kyu Sung Jeong, Jae Yeol Lee, Sang Min Lim, Jae Wook Lee, Ae Nim Pae

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)405-422
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume157
DOIs
Publication statusPublished - 2018 Sep 5

Fingerprint

src Homology Domains
Inositol
Alzheimer Disease
Phosphoric Monoester Hydrolases
Derivatives
Neurodegenerative diseases
Lead compounds
Phosphatases
crizotinib
protein phosphatase inhibitor-2
Inositol Polyphosphate 5-Phosphatases
Amyloid
Neurodegenerative Diseases
Brain
Screening
Chemical activation
Throughput
Lipids
Data storage equipment

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Lim, Ji Woong ; Kim, Seok Kyu ; Choi, Seo Yun ; Kim, Dong Hoi ; Gadhe, Changdev G. ; Lee, Hae Nim ; Kim, Hyo Ji ; Kim, Jina ; Cho, Sung Jin ; Hwang, Hayoung ; Seong, Jihye ; Jeong, Kyu Sung ; Lee, Jae Yeol ; Lim, Sang Min ; Lee, Jae Wook ; Pae, Ae Nim. / Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 157. pp. 405-422.
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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.",
author = "Lim, {Ji Woong} and Kim, {Seok Kyu} and Choi, {Seo Yun} and Kim, {Dong Hoi} and Gadhe, {Changdev G.} and Lee, {Hae Nim} and Kim, {Hyo Ji} and Jina Kim and Cho, {Sung Jin} and Hayoung Hwang and Jihye Seong and Jeong, {Kyu Sung} and Lee, {Jae Yeol} and Lim, {Sang Min} and Lee, {Jae Wook} and Pae, {Ae Nim}",
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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 2018, 'Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease', European Journal of Medicinal Chemistry, vol. 157, pp. 405-422. https://doi.org/10.1016/j.ejmech.2018.07.071

Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease. / Lim, Ji Woong; Kim, Seok Kyu; Choi, Seo Yun; Kim, Dong Hoi; Gadhe, Changdev G.; Lee, Hae Nim; Kim, Hyo Ji; Kim, Jina; Cho, Sung Jin; Hwang, Hayoung; Seong, Jihye; Jeong, Kyu Sung; Lee, Jae Yeol; Lim, Sang Min; Lee, Jae Wook; Pae, Ae Nim.

In: European Journal of Medicinal Chemistry, Vol. 157, 05.09.2018, p. 405-422.

Research output: Contribution to journalArticle

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T1 - Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease

AU - Lim, Ji Woong

AU - Kim, Seok Kyu

AU - Choi, Seo Yun

AU - Kim, Dong Hoi

AU - Gadhe, Changdev G.

AU - Lee, Hae Nim

AU - Kim, Hyo Ji

AU - Kim, Jina

AU - Cho, Sung Jin

AU - Hwang, Hayoung

AU - Seong, Jihye

AU - Jeong, Kyu Sung

AU - Lee, Jae Yeol

AU - Lim, Sang Min

AU - Lee, Jae Wook

AU - Pae, Ae Nim

PY - 2018/9/5

Y1 - 2018/9/5

N2 - 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.

AB - 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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