Dedicated to Prof. Erick M. Carreira on the occasion of his 60th birthday.
Abstract
Targeted protein degradation (TPD) has emerged as an important strategy to target
disease-relevant proteins that were previously considered difficult to drug or even
undruggable. Cereblon (CRBN) plays an outsized role in TPD as a preferred degradation-inducing
effector protein for several reasons, including its anticipated broad protein substrate
scope and its ligandability with drug-like small molecules. Notably, CRBN-based molecular
glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs) have shown success
in clinical trials and, in some cases, as approved drugs. Thus, the interest in CRBN
ligands within the pharmaceutical industry and academia has increased dramatically
in recent years, highlighting the need for robust synthetic approaches towards them.
This short review summarizes tactics and strategies to synthesize CRBN ligands, including
the most recent developments in the field. Particular emphasis is put on the construction
and direct functionalization of key CRBN binding motifs such as glutarimides and dihydrouracils.
1 Introduction
2 Cereblon Ligands with Glutarimide Binding Motif
3 Cereblon Ligands with Dihydrouracil Binding Motif
4 Cereblon Ligands with Other Binding Motifs
5 Conclusions and Outlook
Key words
IMiDs - glutarimide - dihydrouracil - molecular glues - bivalent degraders - cereblon
- drugs - medicinal chemistry
