Heteroaryl Glutarimides and Dihydrouracils as Cereblon Ligand Scaffolds for Molecular Glue Degrader Discovery.

Abstract

Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to target certain proteins that were previously considered to be undruggable. In this context, the discovery of novel CRBN ligands is an important area of ongoing research that holds promise to expand the scope of proteins that can be targeted through this mode of action. Herein, we describe the synthesis and evaluation of CRBN ligands featuring heteroaryl glutarimide and dihydrouracil scaffolds. We identified a subset of heteroaryl glutarimides exhibiting potent CRBN binding and increased chemical stability in cell culture media compared with traditional immunomodulatory drugs (IMiDs). This indicates that the scaffolds described herein could become useful starting points for the discovery of novel molecular glue degraders.