Many cellular events that lead to cancer and the progression of human disease represent aberrant gene expression. Our goal is to access protein-DNA interfaces in the mRNA synthesizing machinery using small molecules and gain external control of transcription pathways. This requires small molecules that can be programmed to bind with high affinity and specificity to a broad repertoire of DMA sites, permeate living human cells, traffic to the nucleus, bind DMA on chromatin and modulate transcription. Down-regulation of transcription can be envisaged to occur by disruption of transcription factor protein-DNA interfaces in promoters of genes by DMA binding small molecules or, alternatively, upregulation of transcription by recruitment of the transcriptional machinery to promoters by small molecule DNA-protein dimerizers. A core specific aim is to explore more fully inhibition of the transcription factor, hypoxia inducible factor (HIF 1a), the principal oxygen sensing molecule in vertebrates. In response to low O2, HIF 1
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