From direct inhibition to induced degradation: clinical progress of MCL-1-targeted interventions in cancer

MCL-1 is the most widely expressed and most rapidly turned over pro-survival member of the BCL-2 family, and the survival of acute myeloid leukemia, multiple myeloma, and many solid tumors depends at least in part on this protein. Several MCL-1-selective inhibitors have entered clinical trials; however, because cardiomyocytes also depend on MCL-1 for survival, direct inhibition has a structurally narrow therapeutic window, single-agent activity has been modest, and no inhibitor has been approved to date. In recent years, the research focus of MCL-1 targeting has shifted from direct occupancy toward downregulation and degradation. CDK9/BET transcriptional inhibition, translational and signaling interventions, pro-ubiquitination, and PROTACs and molecular glues lower MCL-1 within hours and reverse venetoclax resistance, although no degrader has yet entered a registered trial. At present, MCL-1 intervention is positioned mainly as a combination and sequencing component in resistant disease; response prediction relies on dynamic BH3 profiling, and cardiac safety monitoring is a common prerequisite across all routes. Looking forward, the first clinical validation of the degradation paradigm and biomarker-driven patient selection will determine the clinical prospects of this target.