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

Abstract

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.

• Authors: Fuchun Xie, Bingbing X Li, Alina Kassenbrock, Changhui Xue, Xiaoyan Wang, David Z Qian, Rosalie C Sears, Xiangshu Xiao
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 12 Pg. 5075-87 (Jun 25 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26023867 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Cyclic AMP Response Element-Binding Protein
• Naphthalenes

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Breast (drug effects, metabolism, pathology)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclic AMP Response Element-Binding Protein (antagonists & inhibitors, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Naphthalenes (chemistry, pharmacology, therapeutic use)
• Transcriptional Activation (drug effects)