AR-A014418-based dual Glycogen Synthase Kinase 3β/Histone Deacetylase inhibitors as potential therapeutics for Alzheimer's disease

Alzheimer's disease (AD), the most common type of dementia, currently represents an unmet medical need worldwide. It is considered the result of a systemic breakdown of multiple physiological networks which might be adequately tackled by multitarget drugs (MTDs) aimed at restoring the perturbed networks. Accumulating evidence suggests that Glycogen Synthase Kinase 3β (GSK-3β) and Histone Deacetylases (HDACs) synergistically contribute to disease pathogenesis. In a continuation of our efforts to develop MTDs for AD, we manipulated the structure of a previously reported GSK-3β inhibitor, AR-A014418, to develop a new class of dual GSK-3β/HDACs binding agents. Among the 34 synthesized derivatives, compound 19 showed encouraging results, inhibiting GSK-3β (IC₅₀ = 0.04 ± 0.01 μM) HDAC2 (IC₅₀ = 1.05 ± 0.11 μM), and HDAC6 (IC₅₀ = 1.52 ± 0.06 μM). In addition, compound 19 inhibits HDAC2 and 6 activities in cells and blocks tau hyperphosphorylation. Interestingly, it is nontoxic in SH-SY5Y cells up to 100 μM, and exerts neuroprotective effects. Moreover, to better elucidate the mode of action of compound 19, its effects on the molecular pathways of SH-SY5Y cells were studied using a proteome-wide analysis. We uncovered the potential of compound 19, which represents a promising hit for the development of innovative disease-modifying agents.