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Abstract

The work in this thesis examines how hydrophobic modifications within intrinsically disordered regions (IDRs) of transcription factors (TFs), caused by genetic mutations and drug-induced changes, disrupt TF condensation and gene expression programs in various human disease states. I establish as a general paradigm that disease-associated poly-alanine repeat expansions promote the formation of homotypic TF condensates with gel-like material properties, at the expense of heterotypic interactions with other components of the transcriptional apparatus. This effect was elicited by hydrophobic repeat expansions found in the following developmental disorders: synpolydactyly (SPD), cleidocranial dysplasia (CCD), and hand-foot-genital-syndrome (HFGS). Utilizing insights from this paradigm, I hypothesized that the condensation capacity of TFs may be controlled with chemical modifiers of TF-IDRs, in efforts to treat diseases reliant on aberrant transcriptional programs, such as cancer. To this end, this thesis provides evidence that the condensation of an oncogenic transcription factor, the androgen receptor (AR), can be targeted with small molecules that selectively partition into condensates formed by the disordered activation domain of the AR. Increasing the hydrophobicity of the small molecule resulted in higher potency in the arrest of proliferation and AR-driven gene expression programs in a human model of prostate cancer (PCa). Together, these results suggest that hydrophobic modification of transcription factors and small molecules that partition into condensates can be leveraged for therapeutic intent.