title: 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.forename: Fuchun
authors.initials: F
authors.lastname: Xie
authors.forename: Bingbing X
authors.initials: BX
authors.lastname: Li
authors.forename: Alina
authors.initials: A
authors.lastname: Kassenbrock
authors.forename: Changhui
authors.initials: C
authors.lastname: Xue
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D009281:Naphthalenes