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

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