Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Editorial
. 2023 Jun 21:14:653-655.
doi: 10.18632/oncotarget.28440.

Decoding the mechanism behind MCL-1 inhibitors: A pathway to understanding MCL-1 protein stability

Shady I Tantawy, Natalia Timofeeva, Ana Hernandez, Aloke Sarkar, Varsha Gandhi
Editorial

Decoding the mechanism behind MCL-1 inhibitors: A pathway to understanding MCL-1 protein stability

Shady I Tantawy et al. Oncotarget. .
No abstract available

Keywords: AMG-176; AZD5991; B-cell leukemia; MCL-1 inhibitor; MCL-1 protein.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

Authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. Mechanisms of MCL-1 inhibitor-induced MCL-1 protein upregulation, stability, and induction of apoptosis.
Three major pathways (A–C) have been demonstrated for upregulation of MCL-1 protein after treatment with MCL-1 inhibitors. (A) The MCL-1 protein stability is facilitated in part following binding with the MCL-1 inhibitors leading to a conformational change in the protein that enhance MCL-1Thr163 phosphorylation by upstream MEK/ERK signaling pathway. (B) MCL-1 inhibitors treatment enhanced DUB activity and induced Noxa dissociation from MCL-1, followed by rapid Noxa degradation leading to MCL-1 stability through potentiating USP9x: MCL-1 interaction. Additionally, MCL-1 inhibitors reduce the levels of the E3 ligase Mule, resulting in defective ubiquitination of MCL-1. The net effect is seen in an increased stability of the MCL-1 protein. (C) MCL-1 inhibitor binding to MCL-1 protein induces MCL-1 dissociation from BAX/BAK pro-apoptotic protein complex, facilitating their oligomerization resulting in induction of apoptosis. Black arrows indicate potentiating effect, red arrows indicate inhibitory effect. X marks indicate disruption of the normal pathway.
See this image and copyright information in PMC

Comment on

References

    1. Katz C, et al.. Proc Natl Acad Sci U S A. 2008; 105:12277–82. 10.1073/pnas.0711269105. - DOI - PMC - PubMed
    1. Krajewski S, et al.. Am J Pathol. 1995; 146:1309–19. - PMC - PubMed
    1. Beroukhim R, et al.. Nature. 2010; 463:899–905. 10.1038/nature08822. - DOI - PMC - PubMed
    1. Ramsey HE, et al.. Cancer Discov. 2018; 8:1566–81. 10.1158/2159-8290.CD-18-0140. - DOI - PMC - PubMed
    1. Balko JM, et al.. Cancer Discov. 2014; 4:232–45. 10.1158/2159-8290.CD-13-0286. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources