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

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4 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

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Lim, J. W., Kim, S. K., Choi, S. Y., Kim, D. H., Gadhe, C. G., Lee, H. N., Kim, H. J., Kim, J., Cho, S. J., Hwang, H., Seong, J., Jeong, K. S., Lee, J. Y., Lim, S. M., Lee, J. W., & Pae, A. N. (2018). Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease. European Journal of Medicinal Chemistry, 157, 405-422. https://doi.org/10.1016/j.ejmech.2018.07.071