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* and Andrea Milelli*,
{"title":"作为治疗阿尔茨海默病的潜在疗法的首例双非 ATP 竞争性糖原合成酶激酶 3β/ 组蛋白去乙酰化酶抑制剂。","authors":"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* and Andrea Milelli*, ","doi":"10.1021/acschemneuro.4c00061","DOIUrl":null,"url":null,"abstract":"<p >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<sub>50</sub> values in the nanomolar range of concentrations. Among them, compound <b>4</b> 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 <b>4</b> a promising hit for the development of innovative disease-modifying agents.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease\",\"authors\":\"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* and Andrea Milelli*, \",\"doi\":\"10.1021/acschemneuro.4c00061\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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<sub>50</sub> values in the nanomolar range of concentrations. Among them, compound <b>4</b> 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 <b>4</b> a promising hit for the development of innovative disease-modifying agents.</p>\",\"PeriodicalId\":13,\"journal\":{\"name\":\"ACS Chemical Neuroscience\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-05-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Chemical Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00061\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acschemneuro.4c00061","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease
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.
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research