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
Review
. 2015 Jan:145:76-84.
doi: 10.1016/j.pharmthera.2014.08.003. Epub 2014 Aug 27.

Small molecule Mcl-1 inhibitors for the treatment of cancer

Johannes Belmar  1 , Stephen W Fesik  2
Affiliations
Review

Small molecule Mcl-1 inhibitors for the treatment of cancer

Johannes Belmar et al. Pharmacol Ther. 2015 Jan.

Abstract

The Bcl-2 family of proteins serves as primary regulators of apoptosis. Myeloid cell leukemia 1 (Mcl-1), a pro-survival member of the Bcl-2 family of proteins, is overexpressed and the Mcl-1 gene is amplified in many tumor types. Moreover, the overexpression of Mcl-1 is the cause of resistance to several chemotherapeutic agents. Thus, Mcl-1 is a promising cancer target. This review highlights the current progress on the discovery of small molecule Mcl-1 inhibitors.

Keywords: BH3-mimetic; Inhibitors; Mcl-1; Myeloid cell leukemia-1; Small molecule.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
SAR studies at C3 and C6 of S1 led to compound 6.
Figure 2
Figure 2
Fragments derived from the 4 led to two novel classes of Mcl-1 inhibitors.
Figure 3
Figure 3
Merging of fragments derived from two known inhibitors of Mcl-1 and Bcl-XL resulted in novel dual-inhibitors.
Figure 4
Figure 4
Crystal structures of 15 bound to Mcl-1 (A) and to Bcl-XL (B).
Figure 5
Figure 5
Discovery of an N-(4-hydroxynaphthalen-1-yl)sulfonamide Mcl-1 inhibitor.
Figure 6
Figure 6
Synthetic modification of 7-hydroxyquinoline 22 led to compound 23.
Figure 7
Figure 7
Fragments 24 and 26 were elaborated to give compounds 25 and 27.
Figure 8
Figure 8
Cocrystal structures of aryl sulfonamide 28 and salicylate 29 with Mcl-1.
Figure 9
Figure 9
Merging fragments from two distinct classes produced a compound with significantly improved binding affinity.
Figure 10
Figure 10
Cocrystal structures of benzothiophene-2-carboxylic acid 32 (A) and indole-2-carboxylic acid 33 (B).
Figure 11
Figure 11
X-ray structure of Mcl-1 (PDB ID 3MK8).
See this image and copyright information in PMC

References

    1. Abulwerdi FA, Liao C, Mady A, Gavin J, Shen C, Cierpicki T, Stuckey JA, Showalter HDH, Nikolovska-Coleska Z. 3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR and Biological Evaluation. J Med Chem. 2014;57:4111–4133. - PMC - PubMed
    1. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–1337. - PMC - PubMed
    1. Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2008;66:1326–1336. - PMC - PubMed
    1. Albershardt TC, Salerni BL, Soderquist RS, Bates DJ, Pletnev AA, Kisselev AF, Eastman A. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem. 2011;286:24882–24895. - PMC - PubMed
    1. Andersen MH, Becker JC, Straten PT. The antiapoptotic member of the Bcl-2 family Mcl-1 is a CTL target in cancer patients. Leukemia. 2005;19:484–485. - PubMed

MeSH terms

Substances