First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease. / Santini, Alan; Tassinari, Elisa; Poeta, Eleonora; Loi, Manuela; Ciani, Elisabetta; Trazzi, Stefania; Piccarducci, Rebecca; Daniele, Simona; Martini, Claudia; Pagliarani, Barbara; Tarozzi, Andrea; Bersani, Matteo; Spyrakis, Francesca; Danková, Daniela; Olsen, Christian A.; Soldati, Roberto; Tumiatti, Vincenzo; Montanari, Serena; De Simone, Angela; Milelli, Andrea.

In: ACS Chemical Neuroscience, Vol. 15, No. 11, 2024, p. 2099–2111.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Santini, A, Tassinari, E, Poeta, E, Loi, M, Ciani, E, Trazzi, S, Piccarducci, R, Daniele, S, Martini, C, Pagliarani, B, Tarozzi, A, Bersani, M, Spyrakis, F, Danková, D, Olsen, CA, Soldati, R, Tumiatti, V, Montanari, S, De Simone, A & Milelli, A 2024, 'First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease', ACS Chemical Neuroscience, vol. 15, no. 11, pp. 2099–2111. https://doi.org/10.1021/acschemneuro.4c00061

APA

Santini, A., Tassinari, E., Poeta, E., Loi, M., Ciani, E., Trazzi, S., Piccarducci, R., Daniele, S., Martini, C., Pagliarani, B., Tarozzi, A., Bersani, M., Spyrakis, F., Danková, D., Olsen, C. A., Soldati, R., Tumiatti, V., Montanari, S., De Simone, A., & Milelli, A. (2024). First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease. ACS Chemical Neuroscience, 15(11), 2099–2111. https://doi.org/10.1021/acschemneuro.4c00061

Vancouver

Santini A, Tassinari E, Poeta E, Loi M, Ciani E, Trazzi S et al. First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease. ACS Chemical Neuroscience. 2024;15(11):2099–2111. https://doi.org/10.1021/acschemneuro.4c00061

Author

Santini, Alan ; Tassinari, Elisa ; Poeta, Eleonora ; Loi, Manuela ; Ciani, Elisabetta ; Trazzi, Stefania ; Piccarducci, Rebecca ; Daniele, Simona ; Martini, Claudia ; Pagliarani, Barbara ; Tarozzi, Andrea ; Bersani, Matteo ; Spyrakis, Francesca ; Danková, Daniela ; Olsen, Christian A. ; Soldati, Roberto ; Tumiatti, Vincenzo ; Montanari, Serena ; De Simone, Angela ; Milelli, Andrea. / First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease. In: ACS Chemical Neuroscience. 2024 ; Vol. 15, No. 11. pp. 2099–2111.

Bibtex

@article{5aab4f42c5f4470babe063d5f01e3071,
title = "First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer{\textquoteright}s Disease",
abstract = "Despite recent FDA approvals, Alzheimer{\textquoteright}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.",
keywords = "Alzheimer{\textquoteright}s disease, Glycogen Synthase Kinase 3β, Histone Deacetylase, Multitarget Drugs, Neuroprotection",
author = "Alan Santini and Elisa Tassinari and Eleonora Poeta and Manuela Loi and Elisabetta Ciani and Stefania Trazzi and Rebecca Piccarducci and Simona Daniele and Claudia Martini and Barbara Pagliarani and Andrea Tarozzi and Matteo Bersani and Francesca Spyrakis and Daniela Dankov{\'a} and Olsen, {Christian A.} and Roberto Soldati and Vincenzo Tumiatti and Serena Montanari and {De Simone}, Angela and Andrea Milelli",
note = "Publisher Copyright: {\textcopyright} 2024 American Chemical Society.",
year = "2024",
doi = "10.1021/acschemneuro.4c00061",
language = "English",
volume = "15",
pages = "2099–2111",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer’s Disease

AU - Santini, Alan

AU - Tassinari, Elisa

AU - Poeta, Eleonora

AU - Loi, Manuela

AU - Ciani, Elisabetta

AU - Trazzi, Stefania

AU - Piccarducci, Rebecca

AU - Daniele, Simona

AU - Martini, Claudia

AU - Pagliarani, Barbara

AU - Tarozzi, Andrea

AU - Bersani, Matteo

AU - Spyrakis, Francesca

AU - Danková, Daniela

AU - Olsen, Christian A.

AU - Soldati, Roberto

AU - Tumiatti, Vincenzo

AU - Montanari, Serena

AU - De Simone, Angela

AU - Milelli, Andrea

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Glycogen Synthase Kinase 3β

KW - Histone Deacetylase

KW - Multitarget Drugs

KW - Neuroprotection

U2 - 10.1021/acschemneuro.4c00061

DO - 10.1021/acschemneuro.4c00061

M3 - Journal article

C2 - 38747979

AN - SCOPUS:85193466667

VL - 15

SP - 2099

EP - 2111

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 11

ER -

ID: 393771982