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Abstract

In the realm of the development of cancer therapeutics, a significant portion of the human proteome, including over 1600 transcription factors (TFs), is classified as "undruggable". These proteins, often being critical drivers in various cancers, present unique challenges due to their intricate nature and complex interactions with nucleic acids. Despite these obstacles, they offer a very significant therapeutic potential, necessitating innovative approaches for their exploitation in cancer treatment. This thesis showcases the development and application of Computer-Aided Drug Discovery (CADD) in overcoming the challenges associated with targeting proteins that have been previously deemed ‘undruggable’. Through detailed case studies, it reveals the strategic use of CADD in three distinct scenarios: - For the androgen receptor (AR), CADD leverages the existing experimental data to design novel inhibitors with unique chemotypes; - in case of the RNA-binding protein Lin28, CADD orchestrates the entire drug discovery process, from the identification of the binding site to the optimization of lead compounds; - for targeting HOXB13, a relatively uncharted factor, CADD facilitates navigating selectivity challenges, showcasing the adaptability of these tools in unlocking previously unattainable drug targets. Collectively, these three projects illustrate how CADD can assist in the development of inhibitors that disrupt of protein-nucleic acid interactions across various protein families and stages of drug discovery and addressing numerous CADD challenges. Additionally, this work demonstrates that the utility of CADD is deeply intertwined with experimental validation. By seamlessly integrating computational modeling with experimental workflow, this thesis not only introduces novel methodologies for targeting challenging proteins involved into transcription but also highlights the synergistic potential of advancements in both computational and experimental domains. The outcomes of this research extend the horizons of drug discovery, opening up new avenues for cancer treatment and accelerating the development of innovative therapeutic strategies.