ArticleBioorganic & medicinal chemistry2012
Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription.
Article in Bioorganic & medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
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- Mechanistic insights into the activation of ester prodrugs of 666-15.Bioorganic & medicinal chemistry letters · 2020Article
- What turns CREB on? And off? And why does it matter?Cellular and molecular life sciences : CMLS · 2020Review
- Direct Targeting of CREB1 with Imperatorin Inhibits TGFAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- A suite of bioassays to evaluate CREB inhibitors.Methods in enzymology · 2020Article
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- A Lamin-Binding Ligand Inhibits Homologous Recombination Repair of DNA Double-Strand Breaks.ACS central science · 2018Article
- Design, synthesis and evaluation of antitumor acylated monoaminopyrroloquinazolines.Bioorganic & medicinal chemistry letters · 2017Article
- Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription.Bioorganic & medicinal chemistry letters · 2017Article
- Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells.Leukemia · 2016Article
- Systemic Inhibition of CREB is Well-tolerated in vivo.Scientific reports · 2016Article
- Control of CREB expression in tumors: from molecular mechanisms and signal transduction pathways to therapeutic target.Oncotarget · 2016Review
- Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity.Journal of medicinal chemistry · 2015Article
- Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor.ACS medicinal chemistry letters · 2014Article
- Molecular recognition by the KIX domain and its role in gene regulation.Nucleic acids research · 2014Review
- Development of small molecule non-peptide formyl peptide receptor (FPR) ligands and molecular modeling of their recognition.Current medicinal chemistry · 2014Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure-activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX-KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX-KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action.
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