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.
Related in: MedlinePlus
Mentions: The results presented above showed thatthe bioactivities of 3a are very sensitive to structuralmodifications to eitherincrease or decrease its activity. The physicochemical property parameterslike PSA30 and cLogP31 that are associated with cell membrane permeability donot seem to be the major determinants. For example, compounds 3h–j bear similar PSA, but their bioactivitiesdo not correlate with their cLogP (Table 1).To identify the structural basis for the observed bioactivity differencesamong 3a and 3h–j, weperformed conformational searches to identify their global conformationalminima using MacroModel. The conformational ensemble was generatedby systematically rotating all the rotatable bonds in 3a and 3h–j. The identified globalconformational minima are shown in Figure 3. All the four compounds form an intramolecular hydrogen bond betweenthe protonated ammonium nitrogen and amide carbonyl oxygen. However,the more potent CREB inhibitors 3h and 3i adopt a more compact conformation by forming π–πstacking interaction between one of the naphthyl rings and chlorophenylring (Figure 3). On the other hand, the samenaphthyl ring in the less potent compounds 3a and 3j do not form π–π stacking interactionwith the chlorophenyl ring by assuming a more extended conformationat their global minima. These differences suggest that the uniqueconformation associated with 3h and 3i maycontribute to their potent CREB inhibitory activity and antiproliferativeactivity.