Aristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes

Choi, Min; Kim, Ae-Kyeong; Ham, Youngwook; Lee, Joo‐Youn; Kim, Dae-Yong; Yang, Ansook; Jo, Min Ju; Yoon, Eunyoung; Heo, Jung-Nyoung; Han, Sang‐Bae; Ki, Min-Hyo; Lee, Kyu-Sun; Cho, Sungchan

doi:10.1016/j.phymed.2021.153695

Cited by 13 publications

(10 citation statements)

References 67 publications

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“…Aristolactam AIIIA 37 and Aristolactam BIII (4). 38 Aristolactam AIIIA and BIII have been identified as potent inhibitors of DYRK1A with IC 50 values of 80 and 9.7 nM, respectively. Aristolactam BIII has been modeled on the basis of the cocrystal structure of DYRK1A with the bromo version of compound 5j (7) (PDB: 4YLL).…”

Section: ■ Resultsmentioning

confidence: 99%

“…Curcumin (38). Curcumin is a widely studied natural product extracted from the medicinal plant Curcuma longa.…”

Section: ■ Resultsmentioning

confidence: 99%

“…If the compound is active, we then recommend the use of a set of more selective and structurally different products. We strongly advise against the use of the multitarget (kinases and nonkinases) compounds, such as harmine (14), curcumin (38), and EGCG (42), which qualify as pan-assay interference compounds (PAINS) 30 [this does not exclude the possibility that cleaner derivatives can be derived from these natural substances, as illustrated by AnnH75 (3) derived from harmine (14)].…”

Section: ■ Resultsmentioning

confidence: 99%

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Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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Section: ■ Resultsmentioning

confidence: 99%

“…Curcumin (38). Curcumin is a widely studied natural product extracted from the medicinal plant Curcuma longa.…”

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

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Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…Whole-cell extracts were prepared and subjected to western blot analysis with the appropriate antibodies as described previously ( Choi et al, 2021 ). Anti-spike RBD (1:1000, Sino Biological, Beijing, China, Cat.# 40592-T62), anti-ACE2 (1:1000, Abcam, Cambridge, UK, Cat.# ab108252), anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (1:5000, Santa Cruz Biotechnology, CA, USA, Cat.# sc-51905), anti-mouse (1:5000, Santa Cruz Biotechnology, Cat.# sc-516102), and anti-rabbit (1:5000, Enzo Biochem, NY, USA, Cat.# ADI-SAB-300-J) antibodies were used.…”

Section: Methodsmentioning

confidence: 99%

The SpACE-CCM: A facile and versatile cell culture medium-based biosensor for detection of SARS-CoV-2 spike-ACE2 interaction

Ham

Cho

Kim

et al. 2023

Biosensors and Bioelectronics

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“…At the same time, aristolochic amide BIII significantly increased cyclin D1 content in primary fibroblasts of DYRK1A TG mice and increased BrdU labeling by 2–3 times. Experiments further demonstrated that aristolactam BIII could ameliorate cognitive impairment in DYRK1A overexpression mice in vivo [ 71 ]. At present, aristolactam BIII has not been studied in the field of diabetes, but its structure–activity relationship can provide an idea for us to develop DYRK1A inhibitors targeting islet β-cells.…”

Section: Dyrk1a Inhibitors From Natural Productsmentioning

confidence: 99%

Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors

Guo

Yao

et al. 2022

Metabolites

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The pathogenesis of diabetes mellitus is characterized by insulin resistance and islet β-cell dysfunction. Up to now, the focus of diabetes treatment has been to control blood glucose to prevent diabetic complications. There is an urgent need to develop a therapeutic approach to restore the mass and function of β-cells. Although exogenous islet cell transplantation has been used to help patients control blood glucose, it is costly and has very narrow application scenario. So far, small molecules have been reported to stimulate β-cell proliferation and expand β-cell mass, increasing insulin secretion. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitors can induce human β-cell proliferation in vitro and in vivo, and show great potential in the field of diabetes therapeutics. From this perspective, we elaborated on the mechanism by which DYRK1A inhibitors regulate the proliferation of pancreatic β-cells, and summarized several effective natural DYRK1A inhibitors, hoping to provide clues for subsequent structural optimization and drug development in the future.

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Aristolactam BIII, a naturally derived DYRK1A inhibitor, rescues Down syndrome-related phenotypes

Cited by 13 publications

References 67 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

The SpACE-CCM: A facile and versatile cell culture medium-based biosensor for detection of SARS-CoV-2 spike-ACE2 interaction

Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors

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