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

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.

• Authors: Arnold Bolomsky, Meike Vogler, Murat Cem Köse, Caroline A Heckman, Grégory Ehx, Heinz Ludwig, Jo Caers
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 13 Issue 1 Pg. 173 (12 11 2020) ISSN: 1756-8722 [Electronic] England
• PMID: 33308268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Myeloid Cell Leukemia Sequence 1 Protein
• Small Molecule Libraries

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Drug Development
• Hematologic Neoplasms (drug therapy, metabolism)
• Humans
• Molecular Targeted Therapy
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, metabolism)
• Neoplasms (drug therapy, metabolism)
• Small Molecule Libraries (pharmacology, therapeutic use)