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: A series of structural congenersof 3a shown in Figure 2 was designedto improve its biological activities and physicochemical properties.Compound 3a contains a phenolic hydroxyl group that isa potential site for glucuronidation, which would limit its metabolicstability and bioavailability.18−20 To test if this potential metabolicliability can be removed without compromising bioactivity, compound 3b was designed to interrogate the role of the phenol groupin 3a in contributing to its bioactivity. Compound 3a also has relatively high polar surface area (PSA, 123.2Å2) and high cLogP (5.30) (Table 1). To improve these two physicochemical parameters, compounds 3c,d were designed by removing one of the conjugatedplanar naphthyl rings. Truncating one of the naphthyl ring systemsinto a benzene system decreases the PSA to ∼98 Å2 and cLogP to ∼4.9 (Table 1). Compounds 3e–g were designed to probe the role ofthe primary amino group in 3a. If this primary aminogroup tolerates structural changes, additional functional groups maybe attached to the primary amino group. Analogs 3h–j were designed by varying the lengths of the linker and sidechain to understand their roles in biological activities. As presentedin Table 1, compounds 3e–j show decreased PSA and 3g–i also present decreased cLogP compared to 3a.