From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)

Here we show thedevelopment of heterobifunctional small molecules capable of selectively targeting MCL1 usinga Proteolysis Targeting Chimera (PROTAC) methodology leading to successful degradation. Wehave confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon (CRBN) ubiquitinationpathway, making these PROTACs a first step toward a new class of anti-apoptotic BCL-2 familyprotein degraders.