Design, Synthesis, and Bioactivity of Novel Bifunctional Small Molecules for Alzheimer’s disease

Abstract

The abnormal phosphorylation of the τ-protein is a typical early pathological feature of Alzheimer’s disease (AD). The excessive phosphorylation of the τ-protein in the brain causes the formation of neurofibrillary tangles (NFTs) and increases the neurotoxicity of amyloid-β (Aβ). Thus, targeting the τ-protein is considered a promising strategy for treating AD. Herein, we designed and synthesized a series of molecules containing bifunctional groups to recognize the τ-protein and the E3 ligase. The molecules were examined in vitro , and their effects were tested on PC12 cells. In addition, we further studied the pharmacokinetics of compound I3 in healthy rats. Our data showed that compound I3 could effectively degrade τ-protein, reduce Aβ-induced cytotoxicity, and regulate the uneven distribution of mitochondria, which may open a new therapeutic strategy for the treatment of AD.

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

“…Excessive tau phosphorylation enhances the formation of neurofibrillary tangles (NFTs) containing tau and the neurotoxicity of Aβ. Anti-tau small molecule-based PROTACs with a tau ligand (THK5105 derivative) and a CRBN ligand, that is, compound I3, showed tau degradation and reduced Aβ-induced cytotoxicity in in vitro assay using the PC12 cells [ 35 ].…”

Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders

“…Furthermore, intracerebroventricular or subcutaneous administration of C004019 promoted a sustained tau clearance in vivo [200]. Another example is compound I3, a CRBN-based degrader with a THK5105 derivative as a tau ligand, where tau degradation has been demonstrated in vitro using PC12 cells [201].…”