{Reference Type}: Review
{Title}: Dual-target inhibitors of cholinesterase and GSK-3β to modulate Alzheimer's disease.
{Author}: He J;Tam KY;
{Journal}: Drug Discov Today
{Volume}: 29
{Issue}: 4
{Year}: 2024 Apr 8
{Factor}: 8.369
{DOI}: 10.1016/j.drudis.2024.103914
{Abstract}: Alzheimer's disease (AD) is a neurodegenerative disease that affects over 55 million patients worldwide. Most of the approved small-molecule drugs for AD have been designed to tackle a single pathological hallmark, such as cholinergic dysfunction or amyloid toxicity, and thus may not fully address the multifactorial nature of the disease. Inhibition of both cholinesterase and glycogen synthase kinase-3β (GSK-3β) has emerged as a promising strategy to modulate AD. However, the dual inhibition of these two targets posts challenges in molecular design: issues related to target engagements and biopharmaceutical properties in particular must be overcome. In this review, we discuss the physiopathological roles and structures of cholinesterase and GSK-3β as well as recently reported dual-target inhibitors. We critically evaluate the current status of the discovery of dual-target inhibitors of cholinesterase and GSK-3β, and highlight further perspectives.