First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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 IC50 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.
Originalsprog | Engelsk |
---|---|
Tidsskrift | ACS Chemical Neuroscience |
Vol/bind | 15 |
Udgave nummer | 11 |
Sider (fra-til) | 2099–2111 |
ISSN | 1948-7193 |
DOI | |
Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This research was supported by the University of Bologna (Grant RFO and ALMA IDEA 2022 - NextGenerationEU), PRA_2022_60 Ateneo Project of University of Pisa, Next Generation EU \u2013 National Recovery and Resilience Plan (Piano Nazionale di Ripresa e Resilienza, NRRP) \u2013 Mission 4 Component 2 Investment 1.4 \u2013 Ministry of University and Research (MUR) Call No. 3277, Project Code ECS_00000017, MUR Directoral Decree no. 1055, 23 June 2022, CUP B83C22003930001, project title \u201CTuscany Health Ecosystem \u2013 THE\u201D, Spoke 8, University of Turin (SPY_RILO_21_01, SPY_RILO_22_01) and Independent Research Fund Denmark\u2013Technical and Production Sciences (0136-00412B, C.A.O.)
Publisher Copyright:
© 2024 American Chemical Society.
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