MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Journal of Hematology & Oncology

Jo Caers¹  Meike Vogler¹  Grégory Ehx²  Murat Cem Köse²  Caroline A. Heckman³  Arnold Bolomsky⁴  Heinz Ludwig⁴ 

[1] Department of Clinical Hematology, GIGA-I3, University of Liège, CHU De Liège, 35, Dom Univ Sart Tilman B, 4000, Liège, Belgium;Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany;Institute for Molecular Medicine Finland—FIMM, HiLIFE—Helsinki Institute of Life Science, iCAN Digital Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland;Wilhelminen Cancer Research Institute, Wilhelminenspital, Vienna, Austria;

关键词: Myeloid cell leukemia 1;    MCL-1;    BCL-2;    Dependency;    Inhibitor;    Apoptosis;    Cancer;    Leukemia;    Myeloma;    Lymphoma;    Melanoma;   

DOI  :  10.1186/s13045-020-01007-9

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY