A Target Enablement Package for the Inhibition of SHIP1 as a Therapeutic Strategy for the Treatment of Alzheimer’s Disease

• DOI: 10.1002/alz.068781
• Publication Date: 2022-12-20T15:48:01Z
• Authors: Timothy I Richardson; Cynthia D Jesudason; Karen L Lobb; Gregory L Durst; Brent Clayton; Steven M Massey; Daniel E Beck; Zhong‐Yin Zhang; Jiajun Dong; Jianping Lin; Jinmin Miao; Karson S Putt; Andrew D Mesecar; Adam K Hamdani; Emma K Lendy; Sarah Souza; Marlene Jacobson; Jerry Di Salvo; Shaoyou Chu; Emily R Mason; Adrian L Oblak; Disha Soni; Sara K Quinney; Larissa L Silva; Murugesh Kandasamy; Andrea R Masters; Stacey J Sukoff R...; Suzanne Doolen; Kun Huang; Jie Zhang; Bruce T Lamb; Alan D Palkowitz
• Keywords: High-Content Screening

Abstract Background Recent evidence including GWAS and differential gene expression comparing normal to affected Alzheimer’s brain tissue have identified risk protective variants in genes such as TREM2, PLCG2 INPP5D that are essential microglia function. encodes SHIP1, a multi‐domain protein with phosphatase converts PI(3,4,5)P 3 PI(3,4)P 2 , SH2 domain interacts receptor ITAMs competes SYK, proline rich region binds many other proteins. SHIP1 therefore limits activation multiple ways. Inhibition of early disease would increase microglial functions reduce the rate progression cognitive decline patients. Method We performed screen 50K compounds at phosphatase, analyzed publicly available fragment‐based screen, evaluated inhibitors reported literature. utilized malachite green assay PtdIns(3,4,5)P ‐diC8 Ptase‐C2 measure inhibitory potency. A Cellular Thermal Shift Assay was used confirm target engagement cells. high‐content imaging measuring phagocytosis, cell number, nuclear intensity implemented using BV2 HMC3 lines characterize cellular pharmacology cytotoxicity. Mouse were assayed demonstrate similar activity primary Inhibitors predicted drug‐like properties subjected assays solubility, permeability, mouse microsomal stability. physiological based pharmacokinetic model compared measured exposure vivo for select upon oral administration mice. Result been head‐to‐head set relevant both enzyme inhibition activation. Structurally distinct, novel, selective discovered. The mode action, determined. Pharmacokinetic profiles determined sufficient potency studies Conclusion is novel therapeutic strategy treatment Alzheimer’s. structurally distinct molecular scaffolds varying degrees inhibition, activity, Recommendations use probe molecules validation development lead‐like clinical will be made.