Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines

Abstract

To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.

Keywords: Cereblon; IMiDs; Molecular glue; New ligand space; PROTAC; Thio-Michael addition.