Rational optimization of a transcription factor activation domain inhibitor

Abstract

Transcription factors are among the most attractive therapeutic targetsbut are considered largely ‘undruggable’ in part due to the intrinsicallydisordered nature of their activation domains. Here we show that thearomatic character of the activation domain of the androgen receptor, atherapeutic target for castration-resistant prostate cancer, is key for itsactivity as transcription factor, allowing it to translocate to the nucleusand partition into transcriptional condensates upon activation byandrogens. On the basis of our understanding of the interactions stabilizingsuch condensates and of the structure that the domain adopts uponcondensation, we optimized the structure of a small-molecule inhibitorpreviously identified by phenotypic screening. The optimized compoundshad more affinity for their target, inhibited androgen-receptor-dependenttranscriptional programs, and had an antitumorigenic effect in modelsof castration-resistant prostate cancer in cells and in vivo. These resultssuggest that it is possible to rationally optimize, and potentially even todesign, small molecules that target the activation domains of oncogenictranscription factors