Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

Ogawa, Yasushi; Nonaka, Y.; Goto, Toshiyasu; Ohnishi, Eiji; Hiramatsu, Toshiyuki; Kii, Isao; Yoshida, Midori; Ikura, Teikichi; Onogi, Hiroshi; Shibuya, H.; Hosoya, Takamitsu; Ito, Nobuyasu; Hagiwara, Masatoshi

doi:10.1038/ncomms1090

Cited by 235 publications

(269 citation statements)

References 57 publications

Supporting

Mentioning

259

Contrasting

Order By: Relevance

“…Harmine significantly inhibited self-renewal in most of the primary lines ( Figure 6A). As shown in Figure 6B, similar effects were obtained with another DYRK1A inhibitor, INDY, a benzothiazole compound (34). Notably, neither harmine nor INDY greatly suppressed self-renewal in the DYRK1A-negative GBM1.…”

Section: Dyrk1a Modulates Egfr Protein Levels and The Self-renewal Ofsupporting

confidence: 70%

See 1 more Smart Citation

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

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

Self Cite

123

149

View full text Add to dashboard Cite

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.

show abstract

Section: Dyrk1a Modulates Egfr Protein Levels and The Self-renewal Ofsupporting

confidence: 70%

“…Harmine hydrochloride (TCI Europe) and INDY (34) were resuspended in water and DMSO, respectively. They were used at a final concentration of 20 μM unless otherwise noted.…”

Section: Reagentsmentioning

confidence: 99%

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

Pozo

Zahonero²,

Fernández³

et al. 2013

J. Clin. Invest.

Self Cite

123

149

View full text Add to dashboard Cite

show abstract

“…The plant alkaloid harmine, which was used in the current study, displays specificity for DYRK1A (39), but its strong inhibitory effect on monoamine oxidase A and hallucinogenic properties unfortunately limit its use in patients (40). A recently described synthetic inhibitor of DYRK1A, INDY, was found to be active in several in vitro and in vivo models and may show an improved toxicity profile (41). Further support for the concept of quiescence inhibition as a strategy for cancer therapy stems from a previous study in ovarian cancer (42).…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

“…Increased Dyrk1a activity, as we found on the PamGene STK substrate chip for CA5 T cells, is thus compatible with the idea that latently infected T cells exhibit a G 0 /anergy-associated phenotype that renders them unresponsive. Dyrk1a can be targeted with high specificity using either (1Z)-1-(3-ethyl-5-hydroxy-2(3H)-benzothiazolylidene)-2-propanone (INDY) or proINDY (62). The data for INDY/proINDY effects on latent HIV-1 infection are shown in Fig.…”

Section: Shown Are Nf-b Kinetic Profiles For Unstimulated Controls (Cmentioning

confidence: 99%

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Seu

Sabbaj

Duverger

et al. 2015

J Virol

View full text Add to dashboard Cite

The extreme stability of the latent HIV-1 reservoir in the CD4 ؉ memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status. IMPORTANCEThe extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4؉ memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

show abstract

Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A

Cited by 235 publications

References 57 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

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection

Contact Info

Product

Resources

About