title: Identification, synthesis and evaluation of substituted benzofurazans as inhibitors of CREB-mediated gene transcription.
abstract: 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.
authors: Department of Physiology and Pharmacology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Fuchun
authors: F
authors: Xie
authors: Bingbing X
authors: BX
authors: Li
authors: Candice
authors: C
authors: Broussard
authors: Xiangshu
authors: X
authors: Xiao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000737:chemistry* / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: C587540:2-((7-nitrobenzo(c)(1,2,5)oxadiazol-4-yl)thio)pyridine 1-oxide; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D003497:Cyclic N-Oxides; D010069:Oxadiazoles; C020160:benzofurazan; D050882:CREB-Binding Protein
keywords: CBP; CREB; Cancer; Inhibitor; Screening; Selectivity; Structure–activity relationships
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