Identification, synthesis and evaluation of substituted benzofurazans as inhibitors of CREB-mediated gene transcription

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Xie, Fuchun¹  Li, Bingbing X.¹  Broussard, Candice¹  Xiao, Xiangshu¹ 

[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Dept Physiol & Pharmacol, Program Chem Biol, Portland, OR 97239 USA

关键词: CREB;    CBP;    Cancer;    Inhibitor;    Screening;    Selectivity;    Structure-activity relationships;   

DOI  :  10.1016/j.bmcl.2013.07.053

来源: Elsevier

【 摘 要 】

Cyclic-AMP response-element binding protein (CREB) is a stimulus-activated transcription factor. Its transcription activity requires its binding with CREB-binding protein (CBP) after CREB is phosphorylated at Ser133. The domains involved for CREB-CBP interaction are kinase-inducible domain (KID) from CREB and KID-interacting domain (KIX) from CBP. Recent studies suggest that CREB is an attractive target for novel cancer therapeutics. To identify novel chemotypes as inhibitors of KIX-KID interaction, we screened the NCI-diversity set of compounds using a split renilla luciferase assay and identified 2-[(7-nitrobenzo[ c][1,2,5]oxadiazol-4-yl)thio] pyridine 1-oxide (compound 1, NSC228155) as a potent inhibitor of KIX-KID interaction. However, compound 1 was not particularly selective against CREB-mediated gene transcription in living HEK 293T cells. Further structure-activityrelationship studies identified 4-aniline substituted nitrobenzofurazans with improved selectivity. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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