P1: Exploring the chemical space of cereblon ligands: an access to new PROTACs

Due to the induction of neo-protein-protein interactions, such compounds have been coined molecular glues. IMiDs have successfully been employed to generate PROTACs that utilize the human protein quality control system. PROTAC technology has the potential to advance drug development greatly and to expand the druggable proteome.

Gütschow and Steinebach developed IMiD-based homobifunctional PROTACs for self-directed ubiquitination and degradation of CRBN and assembled PROTACs from a CRBN and a von-Hippel-Lindau (VHL) ligand for heterodimerization of two E3 ligases and unidirectional CRBN degradation. In this project, an in-depth medicinal chemistry study on small-molecule E3 ligands will be conducted.

IMiDs, such as pomalidomide, are robust CRBN ligands, but this scaffold offers much room for structural improvement. New CRBN ligands will be designed aimed at (i) high on-target affinity, (ii) limited neosubstrate degradation, and (iii) improved aqueous stability in bio-relevant media. The newly synthesized ligands will be incorporated into exemplary new PROTACs for the targeted degradation of CDK4/6 protein kinases to compare the results of the new PROTACs with previous data.

A detailed physicochemical assessment of PROTACs will be carried out to ensure their quality as potent, cell-permeable compounds. Libraries of building blocks and final PROTACs will be accessible for all groups of the RTG. Improved E3 ligase ligands developed in P1 will be utilized to optimize HDAC degraders (with P2), to design receptor-targeting PROTACs (with P9), as well as for aptamer-based approaches (with P8).