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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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Chemicalstructures of previously reported CREB inhibitors: naphtholAS-E (1) and compounds 2 and 3a. Compound 2 is rapidly transformed into 3a through an O,N-acyl transfer reactionat pH 7.4.
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fig1: Chemicalstructures of previously reported CREB inhibitors: naphtholAS-E (1) and compounds 2 and 3a. Compound 2 is rapidly transformed into 3a through an O,N-acyl transfer reactionat pH 7.4.

Mentions: The proteinkinases leading to CREB activation are frequently overactivated,while the three phosphatases to dephosphorylate CREB are often inactivatedin various cancer cells. Therefore, it was predicted that CREB wouldbe overactivated in cancer cells. Consistent with this prediction,CREB and phosphorylated CREB have been consistently shown to be overexpressedin cancer tissues from brain,8,9 breast,10,11 lung,12 prostate,13 and bone marrow.14 Because ofits aberrant activation in cancer cells, CREB has been pursued asa novel cancer therapeutic target.3 Werecently identified naphthol AS-E (1, Figure 1) as a cell-permeable inhibitor of CREB-mediatedgene transcription through inhibiting KID-KIX interaction,15 the essential protein–protein interactionto activate CREB-dependent gene transcription.4 Consistent with the important roles of CREB in the maintenance ofcancer cells, we found that 1 and its close related derivativesselectively inhibited proliferation of a large panel of cancer celllines from different organs in the low micromolar concentration rangewithout harming normal cells in vitro.16


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)

Chemicalstructures of previously reported CREB inhibitors: naphtholAS-E (1) and compounds 2 and 3a. Compound 2 is rapidly transformed into 3a through an O,N-acyl transfer reactionat pH 7.4.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Chemicalstructures of previously reported CREB inhibitors: naphtholAS-E (1) and compounds 2 and 3a. Compound 2 is rapidly transformed into 3a through an O,N-acyl transfer reactionat pH 7.4.
Mentions: The proteinkinases leading to CREB activation are frequently overactivated,while the three phosphatases to dephosphorylate CREB are often inactivatedin various cancer cells. Therefore, it was predicted that CREB wouldbe overactivated in cancer cells. Consistent with this prediction,CREB and phosphorylated CREB have been consistently shown to be overexpressedin cancer tissues from brain,8,9 breast,10,11 lung,12 prostate,13 and bone marrow.14 Because ofits aberrant activation in cancer cells, CREB has been pursued asa novel cancer therapeutic target.3 Werecently identified naphthol AS-E (1, Figure 1) as a cell-permeable inhibitor of CREB-mediatedgene transcription through inhibiting KID-KIX interaction,15 the essential protein–protein interactionto activate CREB-dependent gene transcription.4 Consistent with the important roles of CREB in the maintenance ofcancer cells, we found that 1 and its close related derivativesselectively inhibited proliferation of a large panel of cancer celllines from different organs in the low micromolar concentration rangewithout harming normal cells in vitro.16

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