Rational molecular glue discovery as new frontier in targeted protein degradation

Recently, targeted protein degradation (TPD) has shown its potential to be a powerful approach in identifying novel therapeutics. With at least 15 clinical programs by end of 2021 and more than 400 preclinical assets, TPD is fundamentally changing the landscape of drug discovery industry. While heterobifunctional molecules represent the largest class of small molecule degraders under preclinical and clinical evaluation, monovalent degraders, also known as “molecular glues”, offer significant advantages, including lower molecular weight, better physicochemical properties, and a much broader target space regardless of ligand availability. Current molecular glue discovery is limited to a few E3 ligases and phenotypic screen. The exciting new opportunity in TPD is to rationally discover novel molecular glues that can induce proximity between any target and a ubiquitin ligase of choice. I would like to discuss new technologies that can potentially enable rationale molecular glue discovery, including advancement of novel computational tools and next generation DNA-encoded compound libraries.