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 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.

近期研究表明，核转录因子环腺苷酸单磷酸应答元件结合蛋白（CREB）在多种癌症中均存在过表达现象。因此，CREB已被开发为一类新型癌症治疗靶点。萘酚AS-E及其密切相关衍生物已被证实可抑制CREB介导的基因转录与癌细胞增殖。此前本研究团队已鉴定出萘甲酰胺3a（naphthamide 3a）作为一类新型化学型别，可抑制CREB的转录活性。为进一步发掘活性更强的CREB抑制剂，本团队设计并合成了3a的一系列结构同源衍生物。通过对这些化合物的生物学活性评价，研究发现化合物3i（666-15）是一种强效且高选择性的CREB介导基因转录抑制剂，其半数抑制浓度（IC50）为0.081 ± 0.04 μM。666-15同时可强效抑制癌细胞增殖，且对正常细胞无毒性作用。在MDA-MB-468异种移植瘤体内模型中，666-15可完全抑制肿瘤生长，且未出现明显毒性反应。上述研究结果进一步证实，CREB作为极具潜力的癌症药物靶点具有重要应用价值。