MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents
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Open Access
REVIEW
MCL‑1 inhibitors, fast‑lane development of a new class of anti‑cancer agents Arnold Bolomsky1, Meike Vogler2, Murat Cem Köse3, Caroline A. Heckman4, Grégory Ehx3, Heinz Ludwig1 and Jo Caers2*
Abstract Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis. Keywords: Myeloid cell leukemia 1, MCL-1, BCL-2, Dependency, Inhibitor, Apoptosis, Cancer, Leukemia, Myeloma, Lymphoma, Melanoma Introduction The intrinsic apoptosis pathway represents the most prominent cell death signaling cascade and is primarily controlled by the BCL-2 family of proteins. This can be split into pro-survival/anti-apoptotic (BCL-2, BCLxL, MCL-1, BCL-W, BFL1), effector (BAK, BAX, BOK), BH3-only activator (BIM, BID, PUMA) and sensitizer (NOXA, BAD, BMF, BIK, Hrk) proteins [1]. The decision between cellular survival and death depends on the precise balance of these anti- and pro-apoptotic proteins. Under homeostasis, anti-apoptotic proteins bind to and sequester both BH3-only activator as well as effector molecules thereby ensuring cellular survival. In the
*Correspondence: [email protected] 2 Department of Clinical Hematology, GIGA-I3, University of Liège, CHU De Liège, 35, Dom Univ Sart Tilman B, 4000 Liège, Belgium Full list of author information is available at the end of the article
presence of a cell death stimuli (e.g., radiation, chemotherapy), however, transcriptional upregulation as well as prost-translational modifications of BH3-only activator and/or sensitizer proteins initiate the intrinsic apoptosis pathway. BH3-only activator and sensitizer proteins directly bind to anti-apoptotic BCL-2 family members with high-affinity which mediates the release of sequestered effector molecules (BAK and BAX). Moreover, free BH3-only activator proteins directly bind to and activate BAK/BAX, which leads to BAK/BAX homo-oligomerizat
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