An inhibitor with GSK3β and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease

Liu, Xin; Lai, Lingyun; Chen, Jiang-Xia; Li, Xiang; Wang, Nan; Zhou, Lijun; Jiang, Xiaowen; Hu, Xiaolong; Liu, Wenwu; Jiao, Xinming; Qi, Zhen-Tong; Liu, Wenjie; Wu, Limeng; Huang, Yaoguang; Xu, Zihua

doi:10.1016/j.neuropharm.2023.109525

Cited by 9 publications

(6 citation statements)

References 36 publications

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“…[29] To detect NFTs formation, we assessed the inhibition of tau protein hyperphosphorylation at the cellular level using a 50 nM OKA-induced SH-SY5Y cell model using a fluorescent probe reported by Zhu et al [30] in 2018 and based on previous work. [31] As shown in Figure 6, the production of NFTs was significantly increased after OKA induction compared to normal SH-SY5Y cells but decreased after pretreatment with selected AR-A014418 (GSK-3β selective inhibitor)…”

Section: Inhibition Of Protein Tau Phosphorylationmentioning

confidence: 87%

Discovery of novel harmine derivatives as GSK‐3β/DYRK1A dual inhibitors for Alzheimer's disease treatment

Qiu,

Feng,

Chen

et al. 2023

Archiv der Pharmazie

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Multitarget‐directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase‐3β (GSK‐3β) and dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK‐3β and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK‐3β and DYRK1A in vitro. ZLQH‐5 was selected as the best compound due to the most potent inhibitory effect against GSK‐3β and DYRK1A. Molecular docking studies demonstrated that ZLQH‐5 could form stable interactions with the ATP binding pocket of GSK‐3β and DYRK1A. In addition, ZLQH‐5 showed low cytotoxicity against SH‐SY5Y and HL‐7702, good blood–brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH‐5 also attenuated the tau hyperphosphorylation in the okadaic acid SH‐SY5Y cell model. These results indicated that ZLQH‐5 could be a promising dual‐target drug candidate for the treatment of AD.

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Section: Inhibition Of Protein Tau Phosphorylationmentioning

confidence: 87%

Discovery of novel harmine derivatives as GSK‐3β/DYRK1A dual inhibitors for Alzheimer's disease treatment

Qiu,

Feng,

Chen

et al. 2023

Archiv der Pharmazie

Self Cite

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“…In addition, it has been observed that DYRK1A is overexpressed in the brains of AD patients [62], further confirming that DYRK1A is involved in AD pathogenesis. At present, several studies have suggested that DYRK1A inhibitors have great potential to treat AD [63][64][65]. However, the development of DYRK1A inhibitors for AD is still at the early stage.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer’s disease: Computational Modeling and Biological Evaluation

Qiu,

Qian,

Guo

et al. 2023

Preprint

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Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays an essential role in tau and Aβ pathology closely related to Alzheimer’s disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitors for clinical use as anti-AD drugs. This is somewhat the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried outin silicoscreening,in vitroassays andin vivoefficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. Byin silicoscreening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compoundQ17(Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compoundQ17and each of three amino acid residues named GLU239, LEU241 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compoundQ17could protect SH-SY5Y cells from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compoundQ17significantly improved cognitive dysfunction in 3×Tg-AD mice, ameliorated pathological changes, and reduced the expression of DYRK1A, GSK-3β and GSK-3β (pSer9), attenuated tau hyperphosphorylation and Aβ deposition as well. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compoundQ17in this study is worthy of further study.Graphic Abstract

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“…Consistently, several DYRK1A inhibitors have demonstrated promising results in rescuing the Aβ and NFTs phenotypes in various in vivo models of AD (Kim et al, 2016;Melchior et al, 2019;Velazquez et al, 2019;Stensen et al, 2021;Zhu et al, 2022;Grygier et al, 2023;Liu et al, 2023). Among these, the most potent inhibitors of DYRK1A from natural sources include β-carboline alkaloid Harmine, the polyphenolic compound in green tea Epigallocatechin-gallate (EGCG), and the marine alkaloid Leucettamine.…”

Section: Autophosphorylation and Substrate Recognition Of Dyrk1a Kinasementioning

confidence: 95%

“…This also presents a challenge for the development of the new DYRK1A-specific inhibitor drugs, although several promising drug candidates are already in the pipeline [reviewed in ( Stotani et al, 2016 ; Pathak et al, 2018 ; Liu T. et al, 2022 )). However, promiscuous targeting of two or more CMGC kinases involved in the AD degeneration could actually be beneficial and warrants further investigation ( Demuro et al, 2021 ; Liu T. et al, 2022 ; Grygier et al, 2023 ; Liu et al, 2023 ). For example, one such promising drug is CX-4945 which not only inhibits DYRK1A but also targets casein kinase II and CLK.…”

Section: Dyrk1a In Human Disease and Therapeutic Developmentmentioning

confidence: 99%

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

Ananthapadmanabhan,

Shows,

Dickinson

et al. 2023

Front. Cell Dev. Biol.

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Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease.

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An inhibitor with GSK3β and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease

Cited by 9 publications

References 36 publications

Discovery of novel harmine derivatives as GSK‐3β/DYRK1A dual inhibitors for Alzheimer's disease treatment

Discovery of novel harmine derivatives as GSK‐3β/DYRK1A dual inhibitors for Alzheimer's disease treatment

Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer’s disease: Computational Modeling and Biological Evaluation

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

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