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 2024-01-19T22:00:39Z 2024-01-19T22:00:39Z 2021-09-03 2018-09-05 0223-5234 https://pubs.kist.re.kr/handle/201004/120923 SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P-2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P-3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid beta 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 GSK3 beta 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. (C) 2018 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER AMYLOID-BETA DISCOVERY PROTEIN PHOSPHATASE MOLECULE TAU PHOSPHORYLATION ACTIVATION PATHOLOGY INSIGHTS Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease Article 10.1016/j.ejmech.2018.07.071 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.157, pp.405 - 422 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 157 405 422 scie scopus 000447480000030 2-s2.0-85051274310 Chemistry, Medicinal Pharmacology & Pharmacy Article AMYLOID-BETA DISCOVERY PROTEIN PHOSPHATASE MOLECULE TAU PHOSPHORYLATION ACTIVATION PATHOLOGY INSIGHTS SH2 domain-containing inositol 5-phosphatase 2 Alzheimer&apos s disease Crizotinib Tau