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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.

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Compound 3i selectively inhibitedtumor cell growth.Shown are antiproliferative dose–response curves of 3i in breast cancer MDA-MB-468 (A) and MDA-MB-231 (B) cells as wellas normal HMEC (C) and HFF (D) cells. The cells were incubated with 3i for 72 h, and then the remaining live cells were quantifiedby the MTT assay.
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fig6: Compound 3i selectively inhibitedtumor cell growth.Shown are antiproliferative dose–response curves of 3i in breast cancer MDA-MB-468 (A) and MDA-MB-231 (B) cells as wellas normal HMEC (C) and HFF (D) cells. The cells were incubated with 3i for 72 h, and then the remaining live cells were quantifiedby the MTT assay.

Mentions: With a potent and specificCREB inhibitor 3i in hand, we tested if it was toxicto normal cells. Previous genetic studies have shown that normal cellstolerate well with reduced levels of CREB.34,35 As shown in Table 2 and Figure 6A,B, 3i potently inhibited growth of MDA-MB-231and MDA-MB-468 cells with GI50 in the midnanomolar concentrationrange. On the other hand, no significant inhibition of growth wasobserved in two different normal cell lines, human mammary epithelialcells (HMEC) and human foreskin fibroblasts (HFF), up to 1 μMconcentration, which is more than 10-fold higher than its GI50 in MDA-MB-231 and MDA-MB-468 breast cancer cells. This selectivetoxicity is in strong contrast to conventional chemotherapeutics likedoxorubicin, which did not show differential toxicity between cancerand normal cells under the same assay conditions.36 Therefore, pharmacological inhibition of CREB’stranscription activity is well tolerated in normal cells, which isconsistent with the idea of cancer cells’ addiction to CREB.3,37,38


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 selectively inhibitedtumor cell growth.Shown are antiproliferative dose–response curves of 3i in breast cancer MDA-MB-468 (A) and MDA-MB-231 (B) cells as wellas normal HMEC (C) and HFF (D) cells. The cells were incubated with 3i for 72 h, and then the remaining live cells were quantifiedby the MTT assay.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Compound 3i selectively inhibitedtumor cell growth.Shown are antiproliferative dose–response curves of 3i in breast cancer MDA-MB-468 (A) and MDA-MB-231 (B) cells as wellas normal HMEC (C) and HFF (D) cells. The cells were incubated with 3i for 72 h, and then the remaining live cells were quantifiedby the MTT assay.
Mentions: With a potent and specificCREB inhibitor 3i in hand, we tested if it was toxicto normal cells. Previous genetic studies have shown that normal cellstolerate well with reduced levels of CREB.34,35 As shown in Table 2 and Figure 6A,B, 3i potently inhibited growth of MDA-MB-231and MDA-MB-468 cells with GI50 in the midnanomolar concentrationrange. On the other hand, no significant inhibition of growth wasobserved in two different normal cell lines, human mammary epithelialcells (HMEC) and human foreskin fibroblasts (HFF), up to 1 μMconcentration, which is more than 10-fold higher than its GI50 in MDA-MB-231 and MDA-MB-468 breast cancer cells. This selectivetoxicity is in strong contrast to conventional chemotherapeutics likedoxorubicin, which did not show differential toxicity between cancerand normal cells under the same assay conditions.36 Therefore, pharmacological inhibition of CREB’stranscription activity is well tolerated in normal cells, which isconsistent with the idea of cancer cells’ addiction to CREB.3,37,38

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