Conformational modulation of intrinsically disordered transactivation domains for cancer therapy.

Intrinsically disordered proteins are implicated in many diseases, but their overrepresentation among transcription factors, whose deregulation can cause disproportionate expression of oncogenes, suggests an important role in cancer. Targeting disordered transcription factors for therapy is considered challenging, as they undergo dynamic transitions and exist as an ensemble of interconverting states. This enables them to interact with multiple downstream partners, often through their transactivation domains (TADs) by the mechanisms of conformational selection, folding-upon-binding, or formation of "fuzzy" complexes. The TAD interfaces, despite falling outside of what is considered "classical" binding pockets, can be conformationally modulated to interfere with their target recruitment and hence represent potentially druggable sites. Here, we discuss the structure-activity relationship of TADs from p53, c-MYC, and the androgen receptor, and the progresses made in modulating their interactions with small molecules. These recent advances highlight the potential of targeting these so far "undruggable" proteins for cancer therapy.