Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions

Saraswati, A Prasanth; Hussaini, S.M. Ali; Krishna, Namballa Hari; Babu, Bathini Nagendra; Kamal, Ähmed

doi:10.1016/j.ejmech.2017.11.103

Cited by 99 publications

(73 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Glycogen synthase kinase-3β (GSK-3β) is a ubiquitous pleiotropic serine/threonine kinase that plays crucial roles in cellular functions, including cell-cycle regulation, differentiation, and proliferation, and gene expression by regulating a wide variety of known targets such as glycogen synthase, τ-protein, and β-catenin [ 1 ]. GSK-3 is involved in cellular signaling, including Wnt and Hedgehog pathways, and in neuronal development, insulin pathways, transcription, cell division, cell survival, and cell death [ 1 , 2 , 3 ]. Due to its multifarious roles, aberrant activity of GSK-3 underlines a variety of disorders including Alzheimer´s disease (AD) [ 4 ], cancer [ 5 ], diabetes [ 6 ], cardiovascular disorders [ 7 ], and psychiatric disorders [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…A number of publications have emerged describing diverse molecules that inhibit GSK-3β, such as manzamine alkaloids [ 20 ], pyrazolopyrimidines [ 21 ], pyridyloxadiazoles [ 22 ], thiadiazolidindiones [ 23 ], maleimides [ 24 ], and paullones (a group of benzazepinones) [ 25 ]. Current advances in the search for GSK-3 inhibitors have been recently reviewed [ 1 , 13 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors

et al. 2018

View full text Add to dashboard Cite

Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors

et al. 2018

View full text Add to dashboard Cite

show abstract

“…GSK-3β se localiza de forma abundante en el sistema nervioso central, donde fosforila a proteínas asociadas a microtúbulos, actividades aberrantes de la proteína desencadenan enfermedades neurodegenerativas tales como Alzheimer y ELA. La hiperactivación de GSK-3β es por tanto un mecanismo desencadenante de la enfermedad [6].…”

Section: Gsk-3unclassified

Fármacos multidiana en el posible tratamiento de la esclerosis lateral amiotrófica

Juberías¹,

González²

2019

DIANAS

View full text Add to dashboard Cite

Palabras clave: esclerosis lateral amiotrófica; TDP-43; GSK-3, CK1, TTBK, fármacos multidiana ResumenLa esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa en la que se produce la muerte de las motoneuronas superiores e inferiores. Aunque tiene un origen desconocido y multifactorial, en el 97% de los pacientes se ha encontrado depósitos de agregados de la proteína TDP-43 (proteína TAR de unión a ADN/ARN). Las funciones de esta proteína nuclear se centran en la regulación del ARN. La proteinopatía de TDP-43 se desencadena con la translocación del núcleo al citoplasma y su hiperfosforilación, lo que da lugar a la acumulación de agregados proteicos y consiguiente degeneración neuronal. Las quinasas que participan en este proceso de fosforilación son: GSK3, CK1, TTBK, CDC7. En este trabajo se propone la modulación de varias quinasas simultáneamente para conseguir un efecto farmacológico más eficaz. Para ello se han evaluado fármacos multidiana, con inhibición dual simultánea en dos de las cuatro quinasas mencionadas, así como combinaciones de monoterapias. Los resultados obtenidos han mostrado sinergia en los tratamientos y validan la utilización de fármacos multidiana en patologías complejas como la ELA. Cita: Lezana Juberías, Esperanza Bertila; Martínez-González, Loreto; Martínez, Ana (2019) Fármacos multidiana en el posible tratamiento de la esclerosis lateral amiotrófica. dianas 8 (2): e201909fa03. ISSN 1886-8746 (electronic) journal.dianas.e201909fa03 http://www3.uah.es/dianas?e201909fa03. URI http://hdl.handle.net/10017/15181 Copyright: © Lezana-Juberías EB, Martínez-González L, Martínez A. Algunos derechos reservados. Este es un artículo open-access distribuido bajo los términos de una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional. http://creativecommons.org/licenses/by-nc-nd/4.0/

show abstract

“…Asp133 and Val135 are the primary amino acids in the ATP catalytic site while T ring region and positive regulator Tyr 216 are the main components in the active site . It consists of the pocket structure of positively charged Arg96, Arg180 and Lys205, but lacks phosphorylated Ser/Thr residues, which require the substrate to provide pre‐phosphorylated Ser/Thr residues . The specific interaction mode between GSK‐3 β and substrate can be determined by allowing the active site of GSK‐3 β to interact with Ser/Thr on the substrate .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

Zhou

Zhang

et al. 2019

Chemistry & Biodiversity

View full text Add to dashboard Cite

Glycogen synthase kinase‐3 (GSK‐3) plays an important regulatory role in various signaling pathways; such as PI3 K/AKT, which is closely related to the occurrence and development of tumors. At present, the most reported active GSK‐3 inhibitors have the same structure: lactam ring or amide structure. To find out the GSK‐3β small molecule inhibitor with novel, safe, efficient and more uncomplicated synthesis method, we analyzed in‐depth reported crystal‐binding patterns of GSK‐3β small molecule inhibitor with GSK‐3β protein, and designed and synthesized 17 non‐reported 3,5‐diamino‐N‐substituted benzamide compounds. Their structures were confirmed by 1H‐NMR, 13C‐NMR, and HR‐MS. The preliminary screening of tumor cytotoxicity of compounds in vitro was detected by MTT, and their structure–activity relationships were illustrated. The results have shown that 3,5‐diamino‐N‐[3‐(trifluoromethyl)phenyl]benzamide (4d) exhibited significant tumor cytotoxicity against human colon cancer cells (HCT‐116) with IC50 of 8.3 μm and showed commendable selectivity to GSK‐3β. In addition, Compound 4d induced apoptosis to some extent and possessed modest PK properties.

show abstract

Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions

Cited by 99 publications

References 116 publications

Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors

Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors

Fármacos multidiana en el posible tratamiento de la esclerosis lateral amiotrófica

Design, Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

Contact Info

Product

Resources

About