2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2

Pagano, Mario A.; Meggio, Flavio; Ruzzene, Maria; Andrzejewska, Mariola; Kazimierczuk, Zygmunt; Pinna, Lorenzo A.

doi:10.1016/j.bbrc.2004.07.067

Cited by 165 publications

(156 citation statements)

References 18 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…To investigate the specificity of this phosphorylation and its inhibition further, we next used a specific inhibitor of CKII, 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) (Pagano et al, 2004). When we treated the MDA-MB-H1-177 cells with DMAT, no effects were seen on the levels of phosphorylation of nm23-H1 (Figure 4e), which also provided further support for the specificity of our phosphoepitope antibody, in its specific recognition of the phosphorylation occurring on serines S122 and S125 of nm23 promoted by CKI.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

Garzia¹,

D’Angelo²,

Amoresano

et al. 2007

Oncogene

View full text Add to dashboard Cite

The combination of an increase in the cAMP-phosphodiesterase activity of h-prune and its interaction with nm23-H1 have been shown to be key steps in the induction of cellular motility in breast cancer cells. Here we present the molecular mechanisms of this interaction. The region of the nm23-h-prune interaction lies between S120 and S125 of nm23, where missense mutants show impaired binding; this region has been highly conserved throughout evolution, and can undergo serine phosphorylation by casein kinase I. Thus, the casein kinase I d-e specific inhibitor IC261 impairs the formation of the nm23-hprune complex, which translates 'in vitro' into inhibition of cellular motility in a breast cancer cellular model. A competitive permeable peptide containing the region for phosphorylation by casein kinase I impairs cellular motility to the same extent as IC261. The identification of these two modes of inhibition of formation of the nm23-H1-h-prune protein complex pave the way toward new challenges, including translational studies using IC261 or this competitive peptide 'in vivo' to inhibit cellular motility induced by nm23-H1-h-prune complex formation during progression of breast cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

Garzia¹,

D’Angelo²,

Amoresano

et al. 2007

Oncogene

View full text Add to dashboard Cite

show abstract

“…We suspected that CK2 might phosphorylate both Ser and Thr residues at these SDTDXD/E clusters (6 Ser and 6 Thr, a total of 12 residues) and therefore generate docking sites for NBS1. To directly test this possibility, we pretreated cells with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), a CK2 inhibitor (26), before irradiation and then examined endogenous MDC1 and NBS1 foci formation. While the MDC1 foci formation was not affected, NBS1 foci were significantly reduced after DMAT treatment (Fig.…”

Section: T He Evolutionarily Conserved Mre11/rad50/nbs1 (Mrn)mentioning

confidence: 99%

MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks

Luo

Lou

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

145

View full text Add to dashboard Cite

The product of the Nijmegen breakage syndrome gene (NBS1) plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50. However, it remains to be determined exactly how NBS1 accumulates at or near DNA double-strand breaks. Here we report that MDC1 directly binds to NBS1 and targets NBS1 to the sites of DNA damage. The MDC1-NBS1 interaction occurs through a specific region (residues 200 -420) of MDC1, which contains multiple consensus casein kinase 2 (CK2) phosphorylation sites. In addition, this interaction requires both the forkhead-associated (FHA) and tandem BRCA1 C-terminal (BRCT) domains of NBS1. Disruption of the MDC1-NBS1 interaction results in failure of NBS1 accumulation at DNA doublestrand breaks and impairment of intra-S checkpoint activation. These studies provide important mechanistic insights as to how MDC1 regulates NBS1 and the intra-S-phase checkpoint in response to DNA damage.complex plays important roles in cell cycle checkpoint signaling and DNA repair. Hypomorphic mutations in NBS1 and MRE11 cause Nijmegen breakage syndrome (NBS) and ataxiatelangiectasia-like disorder (ATLD) respectively (1-3), characterized by developmental defects, immunodeficiency, and a high incidence of cancer. Cells derived from NBS and ATLD patients are hypersensitive to radiation and display impaired intra-Sphase checkpoint activation (1-3), supporting critical roles of this complex in DNA damage response.In response to DNA damage, the MRE11/RAD50/NBS1 complex regulates the activation of ATM, the protein kinase essential for the DNA damage signaling. The key component involved in ATM activation is believed to be NBS1, because NBS1 directly binds to ATM through a very C-terminal motif and modulates ATM autophosphorylation (4-7). Biochemical evidence also suggests that the MRN complex recruits ATM to the vicinity of DNA double-strand breaks (DSBs) and stimulates ATM activation (8). In addition to playing a role in ATM activation, NBS1 also functions downstream of ATM in regulating the intra-S-phase checkpoint (9-11). Besides regulating ATM-dependent phosphorylation of SMC proteins (12, 13), the mechanism by which NBS1 participates in this intra-S-phase checkpoint remains elusive.The human NBS1 gene encodes a 754-aa nuclear protein with an N-terminal forkhead-associated (FHA) domain and breast cancer BRCA1 C-terminal (BRCT) domain. Recently, a second BRCT domain (termed BRCT2) has been identified adjacent to the first BRCT domain (termed BRCT1) (14). Both FHA and BRCT domains mediate protein-protein interaction by recognizing phosphoserine (pSer) and phosphothreonine (pThr)-containing motifs, and many proteins involved in the DNA damage responses contain functional FHA and BRCT domains. Previous reports indicate that retention of NBS1 at DSBs, after DNA damage, is mediated by its interaction with MDC1 (15-19). Moreover, the FHA and BRCT domains of NBS1 are required for its recruitment to DSBs (nuclear foci) after DNA damage (20)(21)(22). Despite these results, it is st...

show abstract

“…A total of 28, 8-week-old male nude mice (Harlan Laboratories GmbH, Eystrup, Germany̸National Atomic Energy Commission, Buenos Aires, Argentina) were injected subcutaneously in the right flank with 4x10 6 SiHa cells in 300 µl PBS. When the tumors reached 30 mm 3 , the mice were randomly assigned into 7 groups (n=4 per group) and were administered placebo, CIGB-300 (days 1-5, 50 or 200 µg), cisplatin (days 1, 3 and 5, 1 or 4 mg/kg), or their combinations, by intraperitoneal (cisplatin) or intratumoral (CIGB-300) routes.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

“…Based on such knowledge, different groups are currently engaged in the quest for highly potent and specific CK2 inhibitors, which may overcome the limitations of first-generation anti-CK2 compounds, such as 5,6-dichloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (DRB), 4,5,6,7-tetrabromo-1H-benzimidazole, 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (3)(4)(5)(6)(7)(8). Such new-generation anti-CK2 compounds are ultimately represented by CX-4945, a small-molecule adenosine triphosphate (ATP) competitor currently in clinical cancer trials (9,10).…”

Section: Introductionmentioning

confidence: 99%

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Perera

Toro

Gorovaya

et al. 2014

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract. CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

show abstract

2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole: a novel powerful and selective inhibitor of protein kinase CK2

Cited by 165 publications

References 18 publications

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Contact Info

Product

Resources

About