QSAR analysis of pyrazolidine-3,5-diones derivatives as Dyrk1A inhibitors

Koo, Kyung Ah; Kim, Nam Doo; Chon, Yong Sog; Jung, Min-Su; Lee, Burm−Jong; Kim, Jung Ho; Song, Woo-Joo

doi:10.1016/j.bmcl.2009.02.062

Cited by 43 publications

(19 citation statements)

References 26 publications

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“…Widely different efficacies have been reported for harmine inhibition of Dyrk1A [18, 20, 23, 25, 29]. In our assay using a truncated wild-type (WT) Dyrk1A (residue 1-497) fused to GST (GST-497) [27] and dynamin 1-derived dynatide 3 as the substrate [30], we obtained an IC 50 of 0.075 μM at 50 μM ATP (Table 1, WT).…”

Section: Resultsmentioning

confidence: 83%

Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)

Adayev

Węgiel

Hwang

2011

Archives of Biochemistry and Biophysics

103

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Harmine is a β-carboline alkaloid. The compound is a potent inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A), a kinase implicated in Down syndrome. In this study, we show that harmine functions as an ATP-competitive inhibitor against Dyrk1A. Our conclusion is supported by kinetic analysis of harmine inhibition as well as by the characterization of a Dyrk1A mutation conferring significant resistance to harmine. The mutation, V306A, is located next to the highly conserved D307 residue in kinases known to coordinate the phosphate groups of ATP through a Mg +2 ion. The V306A mutation offers harmine resistance by differentially altering Dyrk1A affinity for harmine and ATP. The V306A mutation causes no apparent alteration to Dyrk1A activity except for the reduction in ATP affinity. This deficiency could be fully compensated by supplying ATP with a concentration in the physiological range. Our results reveal that harmine inhibits Dyrk1A activity by interacting with residues in the ATPbinding pocket and displacing ATP. Our results also suggest that harmine will be a good lead compound for further designing of selective ATP-competitive Dyrk1A inhibitors through exploration of the ATP-binding pocket of Dyrk1A.

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Section: Resultsmentioning

confidence: 83%

Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)

Adayev

Węgiel

Hwang

2011

Archives of Biochemistry and Biophysics

103

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“…The first targeted approach to develop an inhibitor of DYRK1A resulted in the identification and optimization of pyrazolidinedione compounds that inhibit DYRK1A autophosphorylation with IC 50 values from 0.6–2.5 μ m . [53,55]. These inhibitors remain to be further characterized for their specificity against a broad panel of kinases and their effects in cells or in experimental animals.…”

Section: Synthetic Inhibitorsmentioning

confidence: 99%

Activation, regulation, and inhibition of DYRK1A

2010

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Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Higher than normal levels of DYRK1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. It is therefore important to understand the molecular mechanisms that control the activity of DYRK1A. Here we review the current knowledge about the initial self‐activation of DYRK1A by tyrosine autophosphorylation and propose that this mechanism presents an ancestral feature of the CMGC group of kinases. However, tyrosine phosphorylation does not appear to regulate the enzymatic activity of DYRK1A. Control of DYRK1A may take place on the level of gene expression, interaction with regulatory proteins and regulated nuclear translocation. Finally, we compare the properties of small molecule inhibitors that target DYRK1A and evaluate their potential application and limitations. The β‐carboline alkaloid harmine is currently the most selective and potent inhibitor of DYRK1A and has proven very useful in cellular assays.

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“…Injection of adenoassociated virus vector that encodes inhibitory Dyrk1A shRNA into the striata of Dyrk1A transgenic mice restores motor coordination, attenuates hyperactivity, and improves sensorimotor gating [65]. Several synthetic Dyrk1A inhibitors have also been isolated, although their in vivo efficacy has yet to be tested [66,67].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Function and regulation of Dyrk1A: towards understanding Down syndrome

Park

Song

Chung

2009

Cell. Mol. Life Sci.

Self Cite

180

146

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Down syndrome (DS) is associated with a variety of symptoms, such as incapacitating mental retardation and neurodegeneration (i.e., Alzheimer's disease), that prevent patients from leading fully independent lives. These phenotypes are a direct consequence of the overexpression of chromosome 21 genes, which are present in duplicate due to non-disjunction of chromosome 21. Accumulating data suggest that the chromosome 21 gene product, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1A), participates in the pathogenic mechanisms underlying the mental and other physical symptoms of DS. In this review, we summarize the evidence supporting a role for Dyrk1A in DS, especially DS pathogenesis. Recently, several natural and synthetic compounds have been identified as Dyrk1A inhibitors. Understanding the function and regulation of Dyrk1A may lead to the development of novel therapeutic agents aimed at treating DS.

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QSAR analysis of pyrazolidine-3,5-diones derivatives as Dyrk1A inhibitors

Cited by 43 publications

References 26 publications

Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)

Harmine is an ATP-competitive inhibitor for dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)

Activation, regulation, and inhibition of DYRK1A

Function and regulation of Dyrk1A: towards understanding Down syndrome

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