Generation of potent and selective kinase inhibitors by combinatorial biosynthesis of glycosylated indolocarbazoles

Sánchez, César; Salas, Aaroa P.; Braña, Alfredo F.; Palomino, Martina; Pineda‐Lucena, Antonio; Carbajo, Rodrigo J.; Méndez, Cármen; Morís, Francisco; Salas, José A.

doi:10.1039/b905068j

Cited by 58 publications

(53 citation statements)

References 15 publications

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“…EC-70124 is a product of metabolic engineering of the staurosporine and rebeccanycin biosynthetic pathways. In biochemical kinase assays, EC-70124 acted as a highly effective multikinase inhibitor (37). We show here that both in cells and tumor xenografts, the efficacy of EC-70124 depended on the cell context and activation state of the STAT3 and NF-kB pathways.…”

Section: Discussionmentioning

confidence: 89%

“…Assays interrogating in vitro a large spectrum of kinases in the human kinome revealed that EC-70124 was highly active against IKK and JAK kinases (37,38). EC-70124 was also reported to inhibit NF-kB and JAK/STAT signaling, respectively, in glioblastoma cells (43) and in triple-negative breast cancer cells (38).…”

Section: Ec-70124 Inhibits Nf-kb and Stat3 In Prostate Cancer Cellsmentioning

confidence: 99%

“…Genetic manipulation of the biosynthetic pathways of the glycosylated indolocarbazoles, such as staurosporine and rebeccamycin, was recently reported to give raise to novel compounds retaining the indolocarbazole moiety of rebeccamycin and glycosylation patterns similar to staurosporine (37). Many chimeric compounds acted as potent multikinase inhibitors with similar or higher activity compared with staurosporine when assayed against a wide spectrum of human kinases (37) and unpublished data. In this series of novel glycosylated indolocarbazole compounds, EC-70124 (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…In this series of novel glycosylated indolocarbazole compounds, EC-70124 (Fig. 1A) was of particular interest because it exhibited high activity toward IKK and JAK kinases, such as IKKb and JAK2, with IC 50 in the low nanomolar range (37,38). IKKb phosphorylates IkB, the inhibitory subunit that maintains the NF-kB complex in the inactive state in the cytoplasm (20).…”

Section: Introductionmentioning

confidence: 99%

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EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Civenni

Longoni

Costales

et al. 2016

Molecular Cancer Therapeutics

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Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-kB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKb and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-kB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-kB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 89%

Section: Ec-70124 Inhibits Nf-kb and Stat3 In Prostate Cancer Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Civenni

Longoni

Costales

et al. 2016

Molecular Cancer Therapeutics

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“…Persistent blockade of the NFkB pathway by a smallmolecule inhibitor induces a senescence phenotype in GICs undergoing differentiation In order to translate our findings into a more pharmacologically relevant setting, we used a recently described glycosylated indolocarbazol, 70124 (compound 8), with a potent (o30 pM) IKK2 inhibition activity (Sanchez et al, 2009), in our differentiation model. We showed that treatment of differentiated GICs Consistent with our previous data using the genetic strategies, treatment of differentiating GICs with 70124 resulted in upregulated mRNA expression of neuronal markers Tuj1 and MAP2 and downregulation of GFAP and, to a lesser extent, S100B ( Figure 5c).…”

Section: Downmodulation Of Nfkb Activity Accelerates Maturation Of DImentioning

confidence: 99%

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

et al. 2011

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Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy because of its aggressive behavior. Cancer-initiating or progenitor cells have been described to be the only cell population with tumorigenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells or the early precursors may be beneficial. We have established different cultures of glioblastoma-initiating cells (GICs) derived from surgical specimens and found that, after induction of differentiation, the NFjB transcriptional pathway was activated, as determined by analyzing key proteins such as p65 and IjB and the upregulation of a number of target genes. We also showed that blockade of nuclear factor (NF)jB signaling in differentiating GICs by different genetic strategies or treatment with smallmolecule inhibitors, promoted replication arrest and senescence. This effect was partly mediated by reduced levels of the NFjB target gene cyclin D1, because its downregulation by RNA interference reproduced a similar phenotype. Furthermore, these results were confirmed in a xenograft model. Intravenous treatment of immunodeficient mice bearing human GIC-derived tumors with a novel smallmolecule inhibitor of the NFjB pathway induced senescence of tumor cells but no ultrastructural alterations of the brain parenchyma were detected. These findings reveal that activation of NFjB may keep differentiating GICs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed to promote premature senescence of differentiating GICs by blocking key factors within the NFjB pathway.

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Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

Olano¹,

Méndez²,

Salas³

2014

Natural Products

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Generation of potent and selective kinase inhibitors by combinatorial biosynthesis of glycosylated indolocarbazoles

Abstract: We report the generation of novel glycosylated indolocarbazoles by combinatorial biosynthesis, and the identification of two novel potent and selective compounds inhibitors of JAK2 and Ikkb kinases.

Cited by 58 publications

References 15 publications

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

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