Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer's Disease.

ABSTRACT: Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer's disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and

SUBMITTER: Son SH 

PROVIDER: S-EPMC10037464 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature