Monte Rosa Therapeutics, Massachusetts, United States
Abstract: Many diseases stem from abnormal protein function, and traditional small molecule inhibitor drugs fall short, leaving most proteins undruggable. At Monte Rosa, we have pioneered a transformative approach with our proprietary molecular glue-based targeted protein degradation platform. Our rational-design approach to molecular glue degraders (MGDs) reprograms the cell’s natural protein degradation system to selectively degrade and eliminate hard-to-target proteins.
Our QuEENTM discovery engine integrates high-throughput screening (HTS), mass-spectrometry proteomics, AI/ML, and rational chemistry to discover and develop MGDs that selectively and potently degrade disease-causing proteins. As part of QuEENTM, we have implemented novel high-throughput biochemical and biophysical screening platforms, leveraging recent advancements in lanthanide chelate chemistries.
Here, we will discuss the feasibility and advantages of assays such as High-Throughput Homogeneous Time-Resolved Fluorescence (HTRF) assays to investigate MGD-induced E3 ligase engagement, ternary recruitment, ubiquitylation, and degradation processes. We will show how these assays have enabled us to discover and optimize highly selective, potent MGDs to disease-causing proteins.