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

Protein–protein
interactions (PPIs) have emerged as significant
targets for therapeutic development, owing to their critical nature
in diverse biological processes. An ideal PPI-based target is the
protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor
in cancers such as multiple myeloma where MCL1 levels directly correlate
to disease progression. Current strategies for halting the antiapoptotic
properties of MCL1 revolve around inhibiting its sequestration of
proapoptotic factors. Existing inhibitors disrupt endogenous regulatory
proteins; however, this strategy actually leads to an increase of
MCL1 protein levels. Here, we show the development of hetero-bifunctional
small molecules capable of selectively targeting MCL1 using a proteolysis
targeting chimera (PROTAC) methodology leading to successful degradation.
We have confirmed the involvement of the E3 ligase CUL4A–DDB1
cereblon ubiquitination pathway, making these PROTACs a first step
toward a new class of antiapoptotic B-cell lymphoma 2 family protein
degraders.