Limits...
Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity.

Xie F, Li BX, Kassenbrock A, Xue C, Wang X, Qian DZ, Sears RC, Xiao X - J. Med. Chem. (2015)

Bottom Line: Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells.In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity.These results further support the potential of CREB as a valuable cancer drug target.

View Article: PubMed Central - PubMed

ABSTRACT
Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.

Show MeSH

Related in: MedlinePlus

Compound 3i decreased endogenousCREB target geneexpression. HEK 293T cells were treated with different concentrationsof 3i followed by treatment with forskolin. Then therelative mRNA level of Nurr1/NR4A2 was determinedby qRT-PCR analysis.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493896&req=5

fig4: Compound 3i decreased endogenousCREB target geneexpression. HEK 293T cells were treated with different concentrationsof 3i followed by treatment with forskolin. Then therelative mRNA level of Nurr1/NR4A2 was determinedby qRT-PCR analysis.

Mentions: In the CREB RLuc reporter assay with transfectedHEK 293T cells, compound 3i was very potent in inhibitingCREB’s transcription activity. In order to investigate if 3i also inhibited endogenous CREB target gene expression,the transcript level of nuclear receptor related 1 protein (Nurr1/NR4A2), a well-defined CREB target gene in HEK 293Tcells, was evaluated.17,32 The cells were treated with 3i followed by stimulation with forskolin (10 μM). Thenthe relative mRNA of Nurr1/NR4A2 was determined byquantitative reverse transcription polymerase chain reaction (qRT-PCR).As shown in Figure 4, forskolin robustly stimulated Nurr1/NR4A2 level to ∼31-fold. 3i dose-dependentlyinhibited transcription of Nurr1/NR4A2. Significantinhibition was observed even at 50 nM of 3i. In contrast,the weaker CREB inhibitor 3a only started to show significantinhibition at 1000 nM (Figure S1 in SupportingInformation). These results are consistent with those fromthe CREB reporter assay.


Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity.

Xie F, Li BX, Kassenbrock A, Xue C, Wang X, Qian DZ, Sears RC, Xiao X - J. Med. Chem. (2015)

Compound 3i decreased endogenousCREB target geneexpression. HEK 293T cells were treated with different concentrationsof 3i followed by treatment with forskolin. Then therelative mRNA level of Nurr1/NR4A2 was determinedby qRT-PCR analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493896&req=5

fig4: Compound 3i decreased endogenousCREB target geneexpression. HEK 293T cells were treated with different concentrationsof 3i followed by treatment with forskolin. Then therelative mRNA level of Nurr1/NR4A2 was determinedby qRT-PCR analysis.
Mentions: In the CREB RLuc reporter assay with transfectedHEK 293T cells, compound 3i was very potent in inhibitingCREB’s transcription activity. In order to investigate if 3i also inhibited endogenous CREB target gene expression,the transcript level of nuclear receptor related 1 protein (Nurr1/NR4A2), a well-defined CREB target gene in HEK 293Tcells, was evaluated.17,32 The cells were treated with 3i followed by stimulation with forskolin (10 μM). Thenthe relative mRNA of Nurr1/NR4A2 was determined byquantitative reverse transcription polymerase chain reaction (qRT-PCR).As shown in Figure 4, forskolin robustly stimulated Nurr1/NR4A2 level to ∼31-fold. 3i dose-dependentlyinhibited transcription of Nurr1/NR4A2. Significantinhibition was observed even at 50 nM of 3i. In contrast,the weaker CREB inhibitor 3a only started to show significantinhibition at 1000 nM (Figure S1 in SupportingInformation). These results are consistent with those fromthe CREB reporter assay.

Bottom Line: Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells.In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity.These results further support the potential of CREB as a valuable cancer drug target.

View Article: PubMed Central - PubMed

ABSTRACT
Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. Naphthol AS-E and its closely related derivatives have been shown to inhibit CREB-mediated gene transcription and cancer cell growth. Previously, we identified naphthamide 3a as a different chemotype to inhibit CREB's transcription activity. In a continuing effort to discover more potent CREB inhibitors, a series of structural congeners of 3a was designed and synthesized. Biological evaluations of these compounds uncovered compound 3i (666-15) as a potent and selective inhibitor of CREB-mediated gene transcription (IC50 = 0.081 ± 0.04 μM). 666-15 also potently inhibited cancer cell growth without harming normal cells. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.

Show MeSH
Related in: MedlinePlus