Mcl-1 inhibitors: a patent review

ABSTRACT

Introduction: The myeloid cell leukemia−1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263. Therefore, there has been extensive research and development in the last decade in both academic and industrial settings to address this unmet medical need.

Areas covered: This review covers the research and patent literature of the past 10 years in the field of discovery and development of small-molecule inhibitors of the MCL-1 anti-apoptotic protein.

Expert opinion: Small-molecule strategies to disrupt the protein-protein interactions between MCL-1 and its pro-apoptotic counterparts, such as BAK and BIM, have recently emerged. Several small-molecules based on different scaffolds describe promising in vitro data as MCL-1 selective inhibitors. While many lead compounds remain at the in vitro preclinical development stage, the two most recent patent applications describe promising in vivo data, and one small molecule inhibitor has recently entered into clinical development. It is such an exciting moment that the long awaited clinical studies will generate some insight into the therapeutic potential of this anti-cancer approach, and possibly facilitate the further development of other early stage inhibitors.

KEYWORDS:

• Apoptosis
• cancer
• protein-protein interactions
• MCL-1 inhibitors

Article highlights

• Comprehensively reviewed the discovery and development of MCL-1 inhibitors in both patents and the literature over the past 10 years.

• In detail discussions about the research from Abbvie, Vanderbilt, Michigan, and the most recent disclosures from Servier and Amgen.

• Structurally compared and summarized MCL-1 inhibitors, and discussed their potentials in future developments.

• Patent reviews were illustrated by both general structural formulae and specific key examples.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by the University of Maryland School of Pharmacy.