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Oncol."],"abstract":"<jats:p>Evading apoptosis has been linked to tumor development and chemoresistance. One mechanism for this evasion is the overexpression of prosurvival B-cell lymphoma-2 (BCL-2) family proteins, which gives cancer cells a survival advantage. <jats:italic>Mcl-1<\/jats:italic>, a member of the BCL-2 family, is among the most frequently amplified genes in cancer. Targeting myeloid cell leukemia-1 (MCL-1) protein is a successful strategy to induce apoptosis and overcome tumor resistance to chemotherapy and targeted therapy. Various strategies to inhibit the antiapoptotic activity of MCL-1 protein, including transcription, translation, and the degradation of MCL-1 protein, have been tested. Neutralizing MCL-1\u2019s function by targeting its interactions with other proteins <jats:italic>via<\/jats:italic> BCL-2 interacting mediator (BIM)<jats:sub>S<\/jats:sub>2A has been shown to be an equally effective approach. Encouraged by the design of venetoclax and its efficacy in chronic lymphocytic leukemia, scientists have developed other BCL-2 homology (BH3) mimetics\u2014particularly MCL-1 inhibitors (MCL-1i)\u2014that are currently in clinical trials for various cancers. While extensive reviews of MCL-1i are available, critical analyses focusing on the challenges of MCL-1i and their optimization are lacking. In this review, we discuss the current knowledge regarding clinically relevant MCL-1i and focus on predictive biomarkers of response, mechanisms of resistance, major issues associated with use of MCL-1i, and the future use of and maximization of the benefits from these agents.<\/jats:p>","DOI":"10.3389\/fonc.2023.1226289","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T15:34:07Z","timestamp":1690817647000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":89,"title":["Targeting MCL-1 protein to treat cancer: opportunities and challenges"],"prefix":"10.3389","volume":"13","author":[{"given":"Shady 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