Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer’s Disease

Simone, Angela De; Pietra, Valeria La; Betari, Nibal; Petragnani, Nicola; Conte, Mariarosaria; Daniele, Simona; Pietrobono, Deborah; Martini, Claudia; Petralla, Sabrina; Casadei, Raffaella; Davani, Lara; Frabetti, Flavia; Russomanno, Pasquale; Novellino, Ettore; Montanari, Serena; Tumiatti, Vincenzo; Ballerini, Patrizia; Sarno, Federica; Nebbioso, Angela; Altucci, Lucia; Monti, Barbara; Andrisano, Vincenza; Milelli, Andrea

doi:10.1021/acsmedchemlett.8b00507

Cited by 45 publications

(46 citation statements)

References 32 publications

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“…To a similar extent, De Simone et al have recently proposed a series of HDAC/GSK-3 β inhibitors here represented by compound 52 ( Figure 17 ) [ 126 ]. As already mentioned, GSK-3 β plays a central role in the pathogenic mechanisms of AD through the phosphorylation of pTAU, and the close connection between the latter and HDACs has already emerged.…”

Section: Target Combinations In Mtdl Design Strategy For Admentioning

confidence: 99%

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Maramai

Benchekroun

Gabr

et al. 2020

BioMed Research International

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Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

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Section: Target Combinations In Mtdl Design Strategy For Admentioning

confidence: 99%

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Maramai

Benchekroun

Gabr

et al. 2020

BioMed Research International

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“…Moreover, it promotes neurogenesis and displays immunomodulatory effects. It is nontoxic and protective against H 2 O 2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively [ 183 ].…”

Section: Multi-target Strategy For Admentioning

confidence: 99%

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

Zagórska

Jaromin

2020

Molecules

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Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.

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“…[31] It is well known that typical HDAC inhibitor (eg. SAHA) comprises three fractions: [32] a lipophilic "Cap" site, a zinc-binding group [33] (ZBG) and the linker between them.…”

Section: Chemistrymentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

Gu¹,

Lü²,

Ma³

et al. 2020

Chin. J. Org. Chem.

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Polypharmacology has emerged as a promising approach to drug discovery, especially antitumor drug. This study reports the design, synthesis, and biological evaluation of novel phosphatidylinositol 3-kinases (PI3Ks) and histone deacetylases (HDACs) dual inhibitors on the basis of GSK2126458 under clinical evaluation and vorinostat approved. Among these hybrid molecules, GYB-4 and GYB-5 possessed potent inhibition against both PI3Kα (1.0 and 1.3 nmol/L, respectively) and HDAC1 (4.2 and 4.8 nmol/L, respectively). Antiproliferative assays with HCT116, PC3 and A2780 cell lines subsequently were performed. The structure-activity relationship study will guide to optimization of dual PI3K and HDAC inhibitors.

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Discovery of the First-in-Class GSK-3β/HDAC Dual Inhibitor as Disease-Modifying Agent To Combat Alzheimer’s Disease

Cited by 45 publications

References 32 publications

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

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