Drugging the 'undruggable'. Therapeutic targeting of protein-DNA interactions with the use of computer-aided drug discovery methods

Abstract

Transcription factors (TFs) act as major oncodrivers in many cancers and are frequently regarded as high-value therapeutic targets. The functionality of TFs relies on direct protein-DNA interactions, which are notoriously difficult to target with small molecules. However, this prior view of the 'undruggability' of protein-DNA interfaces has shifted substantially in recent years, in part because of significant advances in computer-aided drug discovery (CADD). In this review, we highlight recent examples of successful CADD campaigns resulting in drug candidates that directly interfere with protein-DNA interactions of several key cancer TFs, including androgen receptor (AR), ETS-related gene (ERG), MYC, thymocyte selection-associated high mobility group box protein (TOX), topoisomerase II (TOP2), and signal transducer and activator of transcription 3 (STAT3). Importantly, these findings open novel and compelling avenues for therapeutic targeting of over 1600 human TFs implicated in many conditions including and beyond cancer.

Keywords: AI; Cancer; Computer-aided drug discovery; Drugs; Protein–DNA interactions; Transcription factor.