First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease
Alan Santini, Elisa Tassinari, Eleonora Poeta, Manuela Loi, Elisabetta Ciani, Stefania Trazzi, Rebecca Piccarducci, Simona Daniele, Claudia Martini, Barbara Pagliarani, Andrea Tarozzi, Matteo Bersani, Francesca Spyrakis, Daniela Danková, Christian A. Olsen, Roberto Soldati, Vincenzo Tumiatti, Serena Montanari, Angela De Simone, Andrea Milelli
Abstract
Despite recent FDA approvals, Alzheimer’s disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β). The synthesized compounds are highly potent GSK-3β, HDAC2, and HDAC6 inhibitors with IC 50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 μM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood–brain barrier and its favorable physical–chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.