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
. 2014 Oct 1;4(10):a014266.
doi: 10.1101/cshperspect.a014266.

Therapeutic strategies to inhibit MYC

Michael R McKeown  1 , James E Bradner  2
Affiliations
Review

Therapeutic strategies to inhibit MYC

Michael R McKeown et al. Cold Spring Harb Perspect Med. .

Abstract

MYC is a master regulator of stem cell state, embryogenesis, tissue homeostasis, and aging. As in health, in disease MYC figures prominently. Decades of biological research have identified a central role for MYC in the pathophysiology of cancer, inflammation, and heart disease. The centrality of MYC to such a vast breadth of disease biology has attracted significant attention to the historic challenge of developing inhibitors of MYC. This review will discuss therapeutic strategies toward the development of inhibitors of MYC-dependent transcriptional signaling, efforts to modulate MYC stability, and the elusive goal of developing potent, direct-acting inhibitors of MYC.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Structural studies of MYC reveal challenges of developing direct-acting inhibitors of (A) MYC Box I (MBI as red ribbon and BIN-1 as white space-fill; PDB: 1MV0) and (B) the MYC:MAX heterodimer (MYC as red ribbon and MAX as white ribbon on white DNA; PDB: 1NKP).
Figure 2.
Figure 2.
Small-molecule disruptors of MYC:MAX heterodimerization.
Figure 3.
Figure 3.
Chromatin-dependent MYC transcriptional signaling. MYC and MAX bind at E-box motifs (boxes) in enhancers and promoters. Protein complex formation causes looping to engage promoters adjacent to MYC target genes (arrow to gene body), inducing RNA Pol II (RNA POL-2) loading to initiation site. Recruitment of TRRAP and histone acetyltransferases (HAT) leads to covalent modification of nucleosomes (clustered gray spheres) with lysine side-chain acetylation (Kac; small black circles). Acetylated, open chromatin is bound by bromodomain-containing proteins, including HATs (CBP, EP300, and GCN5) and BET-family coactivators (BET; yellow). BET bromodomains recruit the P-TEFb elongation complex (cyclin T and CDK-9; cyan), phosphorylates (small green circles) the carboxy-terminal domain of RNA POL-2, causing pause release and leading to elongation.
Figure 4.
Figure 4.
The MYC protein interactome (STRING).
See this image and copyright information in PMC

References

    1. Ahuja P, Zhao P, Angelis E, Ruan H, Korge P, Olson A, Wang Y, Jin ES, Jeffrey FM, Portman M, et al. 2010. Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice. J Clin Invest 120: 1494–1505 - PMC - PubMed
    1. Andresen C, Helander S, Lemak A, Fares C, Csizmok V, Carlsson J, Penn LZ, Forman-Kay JD, Arrowsmith CH, Lundstrom P, et al. 2012. Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding. Nucleic Acids Res 40: 6353–6366 - PMC - PubMed
    1. Baell JB, Holloway GA. 2010. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53: 2719–2740 - PubMed
    1. Berg T. 2008. Inhibition of transcription factors with small organic molecules. Curr Opin Chem Biol 12: 464–471 - PubMed
    1. Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, Boger DL, Vogt PK. 2002. Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc Natl Acad Sci 99: 3830–3835 - PMC - PubMed

Substances