Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription

Bingbing X. Li, Kinrin Yamanaka, Xiangshu Xiao

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6811-6820
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number23
DOIs
StatePublished - Dec 1 2012

Fingerprint

Cyclic AMP Response Element-Binding Protein
Transcription
Structure-Activity Relationship
Antineoplastic Agents
Genes
Derivatives
Phosphotransferases
Cells
Protein Kinases
naphthol AS-E
Neoplasms
G-Protein-Coupled Receptor Kinases
CREB-Binding Protein
Poisons
MCF-7 Cells
Receptor Protein-Tyrosine Kinases
G-Protein-Coupled Receptors
Protein Binding
Tumors
Carrier Proteins

Keywords

  • Cancer
  • CBP
  • CREB
  • Inhibitor
  • Naphthol AS-E
  • Transcription

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription. / Li, Bingbing X.; Yamanaka, Kinrin; Xiao, Xiangshu.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 23, 01.12.2012, p. 6811-6820.

Research output: Contribution to journalArticle

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