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

• Published in: European journal of medicinal chemistry 2018-09, Vol.157, p.405-422
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer's disease; Animals; Crizotinib; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Molecular Structure; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - antagonists & inhibitors; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - metabolism; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; SH2 domain-containing inositol 5′-phosphatase 2; Structure-Activity Relationship; Tau; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.071

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. [Display omitted] •SHIP2 has been suggested as a promising therapeutic target for Alzheimer's disease.•We have developed novel, potent SHIP2 inhibitors by extensive structural modification of crizotinib.•The most promising compound 43 potently inhibited SHIP2 activity in HT22 neuronal cells.•43 possessed favorable physicochemical properties including high brain exposure.