Many human diseases, such as cancer, are caused by dysregulated gene expression. The oversupply or overactivity of one or more transcription factors may be required for the survival, growth and metastatic behavior of all human cancers. The hypothesis of this research program is that cell permeable small molecules which can be programmed to bind a broad repertoire of DNA sequences can disrupt transcription factor-DNA interfaces and modulate aberrant gene expression pathways. This grant combines strong chemistry integrated with transcriptional biology.
Four specific aims are integrated around a common locus, the androgen receptor (AR)-androgen receptor DNA element (ARE), important in the biology of prostate cancer.
In Aim I, high resolution x-ray structures of ARE specific polyamide in complex with ARE-DNA site. Structure elucidation will reveal the allosteric modulation of DNA and the mechanism for AR transcription factor displacement from ARE-DNA.
In Aim II, we will add new heterocycles to our library for DNA recognition by aromatic ring pairs to tune the lipophilicity of ARE binding small molecules to be used in mouse model experiments.
In Aim III, we will map genome-wide the androgen receptor (AR) DNA interactions in human cancer cell lines by ChIP-seq. In addition, we will map the alteration of these interactions in the presence of an AR element specific polyamide. Furthermore, we will map genome-wide ARE specific polyamide-DNA interactions in human cancer cell lines.
Aim I V, we will target the AR-DNA interface in prostate cancer hormone refractory cells. The efficacy will be studied in mice. Solution phase synthesis of gram quantities of the ARE specific polyamide will be scaled up.

Public Health Relevance

Cancer cells have a different and pathological transcriptional pattern compared with normal cells from which they originated. A number of transcription factors are overactive in most human cancers which make them targets for the development of anticancer drugs. Small molecule inhibitors of an overactive process should be a useful mechanism of tumor inhibition. Cell permeable DNA binding small molecules can be programmed to bind a broad repertoire of DNA sequences and mimic the affinity and specificity of DNA binding proteins. Selective inhibition of transcription activity could be achieved by disrupting transcription factor-DNA binding interfaces in the promoters of genes. The goal is reprogramming by small molecules dysregulated transcription responsible for disease. An oversupply or overactivity of one or more transcription factors may be required for the survival, unrestrained growth, and metastatic behavior of all human cancers. Inhibition of excess transcription factor activity on the promoters of dysregulated gene pathways seems a promising approach to anticancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM027681-32
Application #
8288095
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Preusch, Peter C
Project Start
1980-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
32
Fiscal Year
2012
Total Cost
$383,057
Indirect Cost
$135,557
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Xu, Liang; Wang, Wei; Gotte, Deanna et al. (2016) RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif. Proc Natl Acad Sci U S A 113:12426-12431
Mysore, Veena S; Szablowski, Jerzy; Dervan, Peter B et al. (2016) A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity. Mol Cancer Res 14:253-66
Szablowski, Jerzy O; Raskatov, Jevgenij A; Dervan, Peter B (2016) An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors. Mol Cancer Ther 15:608-17
Hargrove, Amanda E; Martinez, Thomas F; Hare, Alissa A et al. (2015) Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. PLoS One 10:e0143161
Kang, JeenJoo S; Dervan, Peter B (2015) A sequence-specific DNA binding small molecule triggers the release of immunogenic signals and phagocytosis in a model of B-cell lymphoma. Q Rev Biophys 48:453-64
Kang, JeenJoo S; Meier, Jordan L; Dervan, Peter B (2014) Design of sequence-specific DNA binding molecules for DNA methyltransferase inhibition. J Am Chem Soc 136:3687-94
Raskatov, Jevgenij A; Puckett, James W; Dervan, Peter B (2014) A C-14 labeled Py-Im polyamide localizes to a subcutaneous prostate cancer tumor. Bioorg Med Chem 22:4371-5
Martínez, Thomas F; Phillips, John W; Karanja, Kenneth K et al. (2014) Replication stress by Py-Im polyamides induces a non-canonical ATR-dependent checkpoint response. Nucleic Acids Res 42:11546-59
Raskatov, Jevgenij A; Szablowski, Jerzy O; Dervan, Peter B (2014) Tumor xenograft uptake of a pyrrole-imidazole (Py-Im) polyamide varies as a function of cell line grafted. J Med Chem 57:8471-6
Yang, Fei; Nickols, Nicholas G; Li, Benjamin C et al. (2013) Antitumor activity of a pyrrole-imidazole polyamide. Proc Natl Acad Sci U S A 110:1863-8

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