MCL1 (Myeloid Cell Leukemia 1) is a critical anti-apoptotic protein belonging to the BCL-2 family, which regulates mitochondrial apoptosis by binding pro-apoptotic proteins like BAX and BAK. Overexpression of MCL1 is frequently observed in various cancers, including hematological malignancies, breast cancer, and lung cancer, where it promotes tumor cell survival, chemoresistance, and disease progression. Its role in maintaining cell survival has made it a compelling therapeutic target.
MCL1-targeting antibodies are experimental agents designed to inhibit MCL1 function, either by blocking its interaction with pro-apoptotic partners or promoting its degradation. Developing selective MCL1 inhibitors has been challenging due to structural similarities with other BCL-2 family proteins and MCL1’s essential role in normal tissue homeostasis (e.g., lymphocyte development). However, advances in structural biology have enabled the design of small-molecule inhibitors and monoclonal antibodies with improved specificity.
Current research focuses on optimizing MCL1 antibody-drug conjugates (ADCs) or combining MCL1 inhibitors with conventional therapies to overcome resistance. Preclinical studies show promising antitumor activity, though clinical translation remains cautious due to potential on-target toxicities. Biomarker-driven approaches are being explored to identify patients most likely to benefit. Overall, MCL1 antibodies represent a frontier in precision oncology, with ongoing trials aiming to balance efficacy and safety in diverse cancer contexts.