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

Adayev, Tatyana; Węgiel, Jerzy; Hwang, Yu-Wen

doi:10.1016/j.abb.2010.12.024

Cited by 103 publications

(79 citation statements)

References 42 publications

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“…We used the β-carboline alkaloid harmine (32) and INDY, a benzothiazole compound (34), with harmine being able to inhibit GBM tumor growth and survival. Harmine and INDY have been shown to bind to the ATP pocket of DYRK1A and inhibit its kinase activity (50). They have limited use in vivo, however, as systemic INDY treatment does not reach the brain and harmine is a potent inhibitor of monoamine oxidase (35).…”

Section: Primary Lines and Culture Conditionsmentioning

confidence: 99%

“…They have limited use in vivo, however, as systemic INDY treatment does not reach the brain and harmine is a potent inhibitor of monoamine oxidase (35). However, molecular docking analysis showed that harmine has many degrees of freedom in the ATP-binding pocket of DYRK1A and that this could be exploited to more selectively inhibit the kinase (50).…”

Section: Primary Lines and Culture Conditionsmentioning

confidence: 99%

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Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

126

149

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Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo-and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumorinitiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

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Section: Primary Lines and Culture Conditionsmentioning

confidence: 99%

Section: Primary Lines and Culture Conditionsmentioning

confidence: 99%

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

126

149

View full text Add to dashboard Cite

show abstract

“…Because DYRK1A is a protein kinase, it is possible to inhibit its activity with pharmacologic agents such as harmine. Harmine is a b-carboline alkaloid with ATP-competitive activity toward DYRK1A (32). We treated GIST882 cells with harmine and found an enhanced cell death in combination with imatinib when compared with imatinib as a single agent (Fig.…”

Section: The Dream Complex Is a Modulator Of The Cellular Response Tomentioning

confidence: 99%

The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis

et al. 2013

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Gastrointestinal stromal tumors (GIST) can be successfully treated with imatinib mesylate (Gleevec); however, complete remissions are rare and patients frequently achieve disease stabilization in the presence of residual tumor masses. The clinical observation that discontinuation of treatment can lead to tumor progression suggests that residual tumor cells are, in fact, quiescent and, therefore, able to re-enter the cell-division cycle. In line with this notion, we have previously shown that imatinib induces GIST cell quiescence in vitro through the APC CDH1 -SKP2-p27Kip1 signaling axis. Here, we provide evidence that imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex, a multisubunit complex that has recently been identified as an additional key regulator of quiescence. Importantly, inhibition of DREAM complex formation by depletion of the DREAM regulatory kinase DYRK1A or its target LIN52 was found to enhance imatinib-induced cell death. Our results show that imatinib induces apoptosis in a fraction of GIST cells while, at the same time, a subset of cells undergoes quiescence involving the DREAM complex. Inhibition of this process enhances imatinib-induced apoptosis, which opens the opportunity for future therapeutic interventions to target the DREAM complex for more efficient imatinib responses. Cancer Res; 73(16); 5120-9. Ó2013 AACR.

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“…Harmine reduced rates of growth and consumption [29] . Harmine is a potent inhibitor of DYRK1A, a kinase implicated in Down syndrome [30] . Harmine inhibits DYRK1A substrate phosphorylation more potently than it inhibits tyrosine autophosphorylation, providing an evidence for a role of DYRK1A in the regulation of neurite formation [31] .…”

Section: Effect Of Harmine On Enzyme Systemsmentioning

confidence: 99%

A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid “Harmine”

Patel

Gadewar

Tripathi

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

215

120

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

Cited by 103 publications

References 42 publications

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis

A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid “Harmine”

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