Transcription factors (TFs) are central regulators of cellular activity. Abnormal TF activity is often a root cause behind diseases, including cancer. However, TFs are largely considered ‘undruggable’ as they lack the deep binding pockets that traditional small molecule drug inhibitors recognize. Luckily, proteins structurally similar to DNA (‘DNA mimics’) exist in nature and bind DNA binding proteins. Because their properties are similar to DNA, I hypothesize that DNA mimics can be re-engineered to bind pathogenic TFs, thereby generating a novel approach to TF-DNA inhibition. Here, I established a general pipeline to engineer novel TF inhibitors using DNA mimic proteins. Computational models predicted how TFs can bind DNA mimic proteins based on their mode of DNA binding. Mutating DNA mimics generated libraries of variants to be screened with high-throughput bacterial screening systems developed to identify novel TF-DNA interaction inhibitors. Once established, this general pipeline could be applied to most TF-DNA interactions.