Elucidating the Mechanism of Small-molecule-induced Protein Degradation for Targeted Cancer Therapy

Abstract

Small-molecule-based targeted cancer therapies should ideally exert complete and sustained pharmacological inhibition of their respective targets. This is often challenging to achieve, given that many targets implicated in cancer lack well defined small-molecule binding pockets. Small-molecules approved for clinical use often target enzymes that feature such binding sites, including kinases, but many non-enzyme cancer targets remain out of reach of the classical targeting modalities. One large class of cancer targets that falls into this category is transcription factors, which have until very recently been considered “undruggable”. However, the recent discovery that thalidomide and its analogs exert their pharmacological effects by inducing degradation of several transcription factors has led to a huge advance in the area of research called targeted protein degradation (TPD). In TPD, small-molecule degraders bridge a target of interest and an E3 ubiquitin ligase, forming a ubiquitination-competent ternary complex that leads to target ubiquitination and subsequent degradation. Because this strategy employs a mechanism of action that is fundamentally different from classical inhibitors, binding affinity of the degrader for the target does not need to be high, and targets with shallow or “absent” binding pockets may be amenable to degradation. Monovalent degraders are of particular interest due to their improved drug-like properties over heterobifunctional degraders. However, most discovery of monovalent degraders has been mostly serendipitous so far and their detailed mechanisms are still elusive in many cases. This thesis research has focused on understanding the mechanism of how monovalent chemical ligands facilitate the destruction of target proteins, which will pave the way to devise general strategies for degrader discovery.