Reductive C(sp²)–C(sp³) Coupling Protocol to Enable Linker Exploration of Cereblon E3-Ligase BRD4 Proteolysis-Targeting Chimeras

Heterobifunctional degraders (also known as proteolysis-targeting chimeras or PROTACs) have emerged in drug discovery as an alternative therapeutic modality for targeting disease-causing proteins that are challenging to modulate with standard protein inhibitors. Almost all current PROTACs under clinical studies use the E3 ligase cereblon (CRBN) to hijack the ubiquitin-proteasome system. In this study, we used high-throughput experimentation to identify new conditions to access carbon-carbon bonds on our CRBN warheads. These efforts led to the discovery that alkyl-connected CRBN binders demonstrate improved cell permeability and reduced neosubstrate activity when compared with their amide counterparts. To further demonstrate the value of this protocol and the resulting alkyl connection point, these conditions were utilized as a final synthetic step to produce a heterobifunctional BRD4 degrader with an improved CRBN neosubstrate selectivity profile compared to its amide counterpart.