Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity.
Bottom Line: 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.
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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Mentions: The selective in vitro toxicity of 3i against cancer cells versus normal cells prompted us to investigateits in vivo antitumor activity. Preliminary toxicity studies showedthat intraperitoneal (ip) injection of 10 mg/kg of 3i is well tolerated in mice (Figure S3).This dose was chosen for in vivo antitumor efficacy studies in theMDA-MB-468 xenografts. The MDA-MB-468 tumor was allowed to grow toan average size of 100 mm3 in nude mice. Then the micewere randomized to receive either vehicle or 3i at 10mg/kg once a day, 5 days per week for 5 weeks by ip injection. Thetumor volumes and body weights were measured 2–3 times/week.The data in Figure 7A showed the tumor growthin the mice treated with 3i was efficaciously inhibitedwith complete tumor stasis. During the same period, the tumor volumein the vehicle-treated group was more than tripled (Figure 7A). The body weights of 3i-treatedanimals and vehicle-treated ones were indistinguishable from eachother during the entire treatment period (Figure 7B), indicating no overt toxicity with this compound treatment.These results are consistent with in vitro studies with compound 3i (Figure 6C,D) where normal cellscould tolerate much higher concentrations of 3i thancancer cells. These data further support the notion that pharmacologicallytargeting CREB is a promising strategy for development of novel cancertherapeutics.