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

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.

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

“…Recently, anticancer drugs targeting CREB have been developed, including the KID/KIX inhibitor KG-501, which blocks the KID-KIX interaction and has a similar activity when compared with the shCREB-silenced or lapatinib-treated cells (21,41). This is in line with data obtained in the present study demonstrating that CREB-specific shRNA, lapatinib, and KG501 treatment caused reversal of the transformed phenotype and growth characteristics of HER-2/neu þ cells.…”

“…Although targeting specific cancer-promoting factors in terms of particular kinases, growth factors and growth factor receptors are currently successfully implemented for the treatment of various cancers (40). The inhibition of the expression of transcription factors, such as CREB, might represent a novel and attractive therapeutic approach for the treament of CREB-overexpressing tumors (41). However, the influence of lapatinib on pCREB expression and function suggests that the tyrosine kinase activity of HER-2/neu is promoting its effects on CREB, as it binds to the intracellular kinase domain (42).…”

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

“…Next, alginate beads loaded with gremlin or VEGF-A 165 were implanted onto the CAMs at 11 days of development. As anticipated, both gremlin and VEGF-A 165 triggered the recruitment of a robust inflammatory cell infiltrate in the CAM stroma that was prevented by the topic administration of a CREB-binding protein-CREB interaction inhibitor that suppresses the transcriptional activity of CREB 42 ( Figure 5B and 5C).…”

Targeting the overexpressed CREB inhibits esophageal squamous cell carcinoma cell growth

“…CREB knockdown inhibited human pre-B acute lymphoblastic leukemia cell growth and induced cell apoptosis (8). Furthermore, several small compounds were reported to target CREB or inhibit its transcriptional activity, exhibited efficient anticancer effect and showed little to no toxicity to normal epithelial cells, fibroblasts or hematopoietic cells (30)(31)(32)(33)(34); 666-15, a CREB inhibitor, showed promising potency against breast cancer in vitro and in a mouse model. Moreover, the mice treated with 666-15 showed no evidence of changes in body weight, complete blood count, blood chemistry profile, cardiac contractility and tissue histology from liver, kidney and heart (34).…”