Identifying novel mechanisms of targeted protein degradation

Lenalidomide, a derivative of thalidomide, was demonstrated to have powerful clinical activity in del(5q) myelodysplastic syndrome and multiple myeloma prior to understanding the mechanism of action of the drug. The Ebert laboratory demonstrated that lenalidomide redirects the activity of the CRL4CRBN E3 ubiquitin ligase to induce ubiquitination and degradation of specific neo-substrates. This a novel mechanism of therapeutic activity enables the targeting of proteins without ligandable pockets, such as transcription factors, that had been considered “undruggable.” (Krönke, et al. Science 2014; Krönke, et al. Nature 2015; Fink, et al. Blood 2018; Sievers, et al. Science 2018)​

Following the demonstration that thalidomide analogs act as molecular glue degraders, we identified a series of additional mechanisms of targeted protein degradation. (Slabicki, et al. Nature 2020a) This includes the identification of small molecule-induced polymerization and degradation of BCL6, a molecular glue that recruits CDK12 to become a substrate receptor for an E3 ubiquitin ligase (Slabicki, et al. Nature 2020b), a general mechanism of nuclear hormone receptor degradation (Tsai, et al. Mol Cell 2023), and a technology using degraders to control CAR-T cells (Jan, et al. Sci Trans Med 2021)​

CR8: Novel Molecular Glue Degrader
BCL6: Small-Molecule-Induced Protein Polymerization