Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3β (GSK-3β) with cellular activity of promoting glucose uptake.

@article{Zhang2014NovelB,
  title={Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3$\beta$ (GSK-3$\beta$) with cellular activity of promoting glucose uptake.},
  author={Peng Zhang and Shufen Li and Yang Gao and Wenbo Lu and Ke Huang and Deyong Ye and Xi Li and Yong Chu},
  journal={Bioorganic \& medicinal chemistry letters},
  year={2014},
  volume={24 24},
  pages={
          5639-5643
        }
}
  • P. Zhang, Shufen Li, +5 authors Yong Chu
  • Published 15 December 2014
  • Chemistry, Medicine
  • Bioorganic & medicinal chemistry letters
Glycogen synthase kinase 3β (GSK-3β) plays a key role in insulin metabolizing pathway and therefore inhibition of the enzyme might provide an important therapeutic approach for treatment of insulin resistance and type 2 diabetes. Recently, discovery of ATP noncompetitive inhibitors is gaining importance not only due to their generally increased selectivity but also for the potentially subtle modulation of the target. These kinds of compounds include allosteric modulators and substrate… 
Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β).
TLDR
The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action.
The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer.
TLDR
Results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in  vivo, might represent a potential candidate for the treatment of OC.
First dual AK/GSK-3β inhibitors endowed with antioxidant properties as multifunctional, potential neuroprotective agents.
TLDR
The identification of compound 5l, as the first dual hAK/hGSK-3β inhibitor reported to date, holds promise for the development of new series of potential therapeutic agents for the treatment of neurodegenerative diseases characterized by an innovative pharmacological profile.
Structural-Based Optimizations of the Marine-Originated Meridianin C as Glucose Uptake Agents by Inhibiting GSK-3β
TLDR
The results suggest that the pyrimidine group of meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.
Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases
TLDR
The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators.
Natural and synthetic bioactive inhibitors of glycogen synthase kinase.
TLDR
An overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation is presented and some clues for the future optimization of these promising molecules to develop specific drugs inhibiting G SKS-3, for the treatment of associated disease conditions are discussed.
Design, synthesis, and biological evaluation of novel (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.
TLDR
The compound f9, the title compound, improved memory and cognitive functions in a mouse model induced by scopolamine and can be considered as a promising lead compound for further investigation in the treatment of AD.
Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery?
TLDR
The reasons behind the development of GSK-3β-directed MTDLs are discussed and some of the recent efforts to obtain these new classes ofMTDLs as potential disease-modifying agents are highlighted.
Revisiting protein kinase–substrate interactions: Toward therapeutic development
TLDR
The advances in understanding how kinases physically interact with their substrates are summarized and the various approaches that can be used to identify them and analyze their binding structures for targeted drug development are discussed.
Microsecond molecular dynamics simulations and dynamic network analysis provide understanding of the allosteric inactivation of GSK3β induced by the L343R mutation
TLDR
Microsecond molecular dynamics simulations and network analysis are performed to elucidate the allosteric inactivation of GSK3β triggered by the L343R mutation, providing a mechanistic explanation of how the L 343R mutation allosterically affects the functional activity of G SK3β.
...
1
2
...

References

SHOWING 1-10 OF 27 REFERENCES
Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β).
TLDR
In vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale, and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.
5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3.
TLDR
Substitute 5-imino-1,2,4-thiadiazoles are reported as the first small molecules able to inhibit GSK-3 in a substrate competitive manner, and are cell permeable, able to decrease inflammatory activation and to selectively differentiate neural stem cells.
Identification of small molecules that inhibit GSK-3beta through virtual screening.
TLDR
The results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors of GSK-3beta inhibitors, and that small molecule can prevent degradation of beta-catenin via G SK-3 beta inhibition.
Exploring the binding sites of glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities.
TLDR
The search for the druggable sites on the enzyme using the fpocket algorithm allowed us to determine the binding sites of different GSK-3 ATP noncompetitive inhibitors, such as manzamine A and the new small molecule VP 0.7, providing evidence for potential allosteric inhibition of GK3.
Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin.
TLDR
The isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor is described and offers new opportunities for designing and developing selective inhibitors with novel mechanisms of action.
Using small molecule GSK3β inhibitors to treat inflammation.
TLDR
The combined anti-proliferative and anti-inflammatory properties of small molecule inhibitors of GSK3β make them an attractive treatment modality towards the control of inflammation.
Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation
TLDR
This review is mainly focused on the new GSK‐3 inhibitors discovered or specifically developed for this enzyme, their chemical structure, synthesis, and structure–activity relationships, with the aim of providing some clues for the future optimization of these promising drugs.
Substrate competitive GSK-3 inhibitors - strategy and implications.
TLDR
It is argued that GSK-3 is a promising drug discovery target and the strategy and practice for developing specific substrate-competitive inhibitors of G SKS-3 are described.
Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes.
TLDR
GSK3 is focused on as a central negative regulator in the insulin signaling pathway, its role in insulin resistance, and the utility of GSK3 inhibitors for intervention and control of metabolic diseases including type 2 diabetes.
Insulin Mimetic Action of Synthetic Phosphorylated Peptide Inhibitors of Glycogen Synthase Kinase-3
TLDR
A novel class of specific phosphorylated peptides inhibitors of GSK-3, which in sharp contrast to other protein kinase inhibitors that are ATP analogs, are substrate-competitive, are presented.
...
1
2
3
...