From direct inhibition to induced degradation: clinical progress of MCL-1-targeted interventions in cancer
Abstract
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.
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BibTeX
@article{liu2026from,
title = {{From direct inhibition to induced degradation: clinical progress of MCL-1-targeted interventions in cancer}},
author = {Shuai Liu and Shan Jiang and Mengjiao Zhang and Weixiao Wang and Huiru Peng and Wei Yang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2010618},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2010618},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From direct inhibition to induced degradation: clinical progress of MCL-1-targeted interventions in cancer
AU - Shuai Liu
AU - Shan Jiang
AU - Mengjiao Zhang
AU - Weixiao Wang
AU - Huiru Peng
AU - Wei Yang
PY - 2026
DA - 2026/11/06
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2010618
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2010618
AB - 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.
SN - 1663-9812
ER -