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Bioorg Med Chem Lett. 2013 Oct 1;23(19):5371-5. doi: 10.1016/j.bmcl.2013.07.053. Epub 2013 Jul 31.

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

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Department of Physiology and Pharmacology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.


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.


CBP; CREB; Cancer; Inhibitor; Screening; Selectivity; Structure–activity relationships

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