An updated patent review of Mcl-1 inhibitors (2020–2022)

ABSTRACT

Introduction

Myeloid leukemia 1 (Mcl−1), an antiapoptotic protein of the Bcl−2 family, is an attractive target for cancer therapy. In recent years, significant progress has been made with regard to Mcl−1 inhibitors, leading to the generation of highly potent Mcl−1 inhibitors that have entered clinical trials.

Areas covered

This review provides an overview of the patent literature between 2020 and 2022 −covering inhibitors, antibody–drug conjugate (ADC), and proteolysis targeting chimera (PROTAC) of Mcl1.

Expert opinion

Despite the great success of Mcl−1 inhibitor development, the on-target toxicity to heart indicated that the BH3 mimetic Mcl−1 inhibitors could have a limited therapeutic window.

Drug combinations of Mcl−1 inhibitors with targeted therapies or chemotherapies may improve safety as they may reduce the dose of Mcl−1 inhibitors. Alternatively, some technologies like ADC and PROTACS could also be utilized to improve the therapeutic window. We envision a precision medicine platform like BH3 profiling or single-molecule pull-down and co-immunoprecipitation platform will enable the tailored use of Mcl−1 inhibitors utilizing the unique molecular information of individual patients.

KEYWORDS:

• Mcl-1
• small molecule inhibitors
• BH3 mimetic
• Bcl-2
• anticancer

Article highlights

• Mcl−1 is a hot target for human cancer treatment.

• A number of highly specific small-molecule Mcl−1 inhibitors have been identified, and some of them have been tested in clinical trials.

• The on-target toxicity of Mcl−1 inhibitors limits its therapeutic window

• Alternative technologies like ADC and PROTACS could also be utilized to improve the therapeutic window.

• A precision medicine platform will enable the tailored use of Mcl−1 inhibitors on individual patients.

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article from Pubmed at https://pubmed.ncbi.nlm.nih.gov and from SciFinder at https://scifinder-n.cas.org.

Author contribution statement

Conceptualization, T. S., and Z. Z.; data curation, J. L., Z. W., and F. Y.; formal analysis, J. L., and F. Y.; Writing-original draft preparation, J. L. and T. S.; Writing-review & editing, T. S., and Z. Z.; funding acquisition, Z. Z. All the authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (82270186, 82073703, and 82273778), the Natural Science Foundation of Liaoning Province (2021-BS-061) and the Fundamental Research Funds for the Central University (DUT22YG223, DUT22YG106, and DUT21RC(3)090).