The goal of the proposed research is to develop small molecule inhibitors of CREB (cAMP-response element binding protein)-mediated gene transcription as potential anticancer agents. Recently, accumulating evidence has revealed that CREB participates in the regulation of immortalization, transformation and metastasis of cancer cells. In some cancer patients (e.g. acute leukemia, prostate cancer and breast cancer), expression of CREB correlated with cancer phenotypes including cancer cell differentiation, metastasis, time to relapse and survival. This suggests that inhibiting the transcription activity of CREB could be a promising strategy for anticancer treatment. Consistent with this hypothesis, expression of a dominant-negative CREB mutant in melanoma and lung cancer cell lines or down-regulating the expression of CREB in leukemia cell lines reduced the transforming phenotypes of the cancer cells. Moreover, delivery of a CRE decoy oligonucleotide into human breast cancer or prostate cancer cells led to significant inhibition of tumor cell growth both in vitro and in vivo while similar experiments in normal cells showed no toxicity. These results indicate that pharmacologically inhibiting CREB activity could be an excellent strategy for cancer treatment. However, small molecule inhibitors of CREB-mediated have not been developed for evaluation of anticancer activity. We recently developed a novel assay to specifically look at CREB-CBP interaction and discovered naphthol AS-E as a small molecule inhibitor of CREB-CBP interaction both in vitro and in cells. Moreover, we found that this compound was able to inhibit cancer cell growth by inducing apoptosis in a number of different cancer cells irrespective of their p53 status. Based on these promising preliminary results, we propose to further evaluate its therapeutic potential and optimize its anticancer activity. The following aims will be addressed: 1) To define the structure-activity relationships (SAR) of naphthol AS-E as an anticancer agent and inhibitor of CREB-CBP interaction by designing and synthesizing analogs with different substitutions on the appendant phenyl ring;2) To develop a novel series of naphthol AS-E derivatives with enhanced potency and aqueous solubility as probes for structural studies;3) To investigate the hypothesis that CREB-mediated gene transcription is required for anticancer activity displayed by naphthol AS-E and its derivatives. Development of small molecule inhibitors CREB-mediated gene transcription will not only lead to potential therapeutics for cancer, but also provide a powerful tool to manipulate CREB's activity in vitro and in vivo to further dissect its biological functions.

Public Health Relevance

The proposed research is to develop chemical inhibitors of CREB-mediated gene transcription. These inhibitors are expected to be potential candidates as anticancer agents for a variety of cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087305-03
Application #
8306277
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$320,166
Indirect Cost
$101,039
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Li, Bingbing X; Gardner, Ryan; Xue, Changhui et al. (2016) Systemic Inhibition of CREB is Well-tolerated in vivo. Sci Rep 6:34513
Mitton, B; Chae, H-D; Hsu, K et al. (2016) Small molecule inhibition of cAMP response element binding protein in human acute myeloid leukemia cells. Leukemia 30:2302-2311
Chao, Bo; Li, Bingbing X; Xiao, Xiangshu (2015) The chemistry and pharmacology of privileged pyrroloquinazolines. Medchemcomm 6:510-520
Kang, Xunlei; Lu, Zhigang; Cui, Changhao et al. (2015) The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat Cell Biol 17:665-77
Rankin, Erinn B; Narla, Anupama; Park, Joseph K et al. (2015) Biology of the bone marrow microenvironment and myelodysplastic syndromes. Mol Genet Metab 116:24-8
Xie, Fuchun; Li, Bingbing X; Kassenbrock, Alina et al. (2015) Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. J Med Chem 58:5075-87
Sakamoto, Kathleen M; Grant, Steven; Saleiro, Diana et al. (2015) Targeting novel signaling pathways for resistant acute myeloid leukemia. Mol Genet Metab 114:397-402
Xie, Fuchun; Li, Bingbing X; Xiao, Xiangshu (2013) Synthesis and Evaluation of an O-Aminated Naphthol AS-E as a Prodrug of CREB-mediated Gene Transcription Inhibition. Lett Org Chem 10:380-384
Chen, Jingjin; Kassenbrock, Alina; Li, Bingbing X et al. (2013) Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine. Medchemcomm 4:1275-1282
Xie, Fuchun; Li, Bingbing X; Broussard, Candice et al. (2013) Identification, synthesis and evaluation of substituted benzofurazans as inhibitors of CREB-mediated gene transcription. Bioorg Med Chem Lett 23:5371-5

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