While classical small molecule drugs modulate their target protein's activity, proximity-inducing compounds modulate their target protein's interactome. Ultimately, this can lead to changes in not only activity but also protein stability or localization. Molecular degraders facilitate the recruitment of an E3-ligase to a target protein thus catalytically triggering target polyubiquitylation and subsequent proteasomal degradation.
This targeted protein degradation (TPD) mode of action results in specific challenges for the development of discovery strategies and requires a fit-for-purpose, comprehensive assay cascade to reliably and specifically identify target degraders from small molecule libraries.
We are developing diverse cell-based TPD screening and validation assays and have identified workflows and assay cascades aimed to systematically discover chemistry acting via the TPD mechanism. Our setup is highly automated and includes 384-well plate-based, homogenous immunoassay as well as high-content imaging to directly quantify levels of target protein and its degradation. Moreover, a signal rescue-type assay is integrated where cell growth is recovered by target degradation, thereby excluding unspecific compounds. Additionally, aiming towards an integrated screening and knowledge platform, we are developing informatic tools and machine learning models for the TPD space.
This presentation will focus on TPD screening workflows and analyse screening performance through examples of targets that are well-known and advanced in the TPD field. Presenters include Johanna Huchting, Principle Scientist, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP and Preethi Soundarya Sathyamurthi, PhD, Senior Scientist, GSK