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Review
. 2022 Jan:75:103756.
doi: 10.1016/j.ebiom.2021.103756. Epub 2021 Dec 20.

Therapeutic targeting of "undruggable" MYC

Victor Llombart  1 , Marc R Mansour  2
Affiliations
Review

Therapeutic targeting of "undruggable" MYC

Victor Llombart et al. EBioMedicine. 2022 Jan.

Abstract

c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC.

Keywords: Cancer; MYC; MYC protein interactors; Small-molecule inhibitors; Therapeutic strategies.

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Conflict of interest statement

Declaration of interests No conflicts of interest.

Figures

Figure 1
Figure 1
MYC regulates all hallmarks of cancer. Oncogenic levels of MYC promote proliferative signalling, inhibition of growth suppression, escaping immune response, tumour inflammation, angiogenesis, genome instability and changes in cellular metabolism; and inhibits cell replicative immortality, metastasis and the escape of programmed cell death.
Figure 2
Figure 2
Structure of MYC protein. A) Intrinsically disordered region prediction for c-MYC (predictor tool PONDR). B) Organization of the main protein domains and conservation across different MYC super-family members. C) X-ray structure of MYC:MAX heterodimer binding DNA (PDB ID: 1NKP).
Figure 3
Figure 3
Schematic of MYC protein interactors. The minimal interaction region between both proteins is mapped. Green boxes represent activators of MYC function. Red boxes represent repressors of MYC activity.
Figure 4
Figure 4
Strategies for direct and indirect small-molecule inhibition of MYC protein.
See this image and copyright information in PMC

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