Targeted Protein Degradation
Dysregulation of gene control is hallmark characteristic of cancer, and individual tumor types are commonly dependent on discrete gene control factors. Research in clinical cancer genetics and functional cancer biology has validated a still growing list of compelling transcriptional addictions with immediate therapeutic relevance. Threatening the clinical impact of these findings is the persistent challenge in the development of direct-acting chemical inhibitors of transcription factors. Transcription factors (TFs) challenge coordinated efforts in ligand discovery, as they often function via protein-protein interactions mediated by large interfacial domains that lack the characteristic features of addressable hydrophobic pockets. Further, many TFs exhibit a multidomain structure, often further complicated by intrinsic disorder or limited biochemical characterization. It is therefore not always clear which domain to target, and commonly the ligandable domain is not responsible for the tumor-associated phenotype. We have therefore established a facile and first all-chemical platform for targeted protein degradation, for the mechanistic study of fast transcriptional biology, target validation and drug discovery.