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.

• Authors: 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
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 157 Pg. 405-422 (Sep 05 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 30103190 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Pyrazoles
• Pyridines
• Crizotinib
• INPPL1 protein, human
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Topics

• Alzheimer Disease (drug therapy, enzymology)
• Animals
• Crizotinib
• Dogs
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Mice
• Microsomes, Liver (drug effects, enzymology)
• Molecular Structure
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (antagonists & inhibitors, metabolism)
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Rats
• Structure-Activity Relationship
• Tumor Cells, Cultured