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.
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.
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|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|
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|Chenoweth, David M; Dervan, Peter B (2010) Structural basis for cyclic Py-Im polyamide allosteric inhibition of nuclear receptor binding. J Am Chem Soc 132:14521-9|
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