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Review
. 2018 Jun 19;23(6):1479.
doi: 10.3390/molecules23061479.

Targeting Transcription Factors for Cancer Treatment

Mélanie Lambert  1 , Samy Jambon  2 , Sabine Depauw  3 , Marie-Hélène David-Cordonnier  4
Affiliations
Review

Targeting Transcription Factors for Cancer Treatment

Mélanie Lambert et al. Molecules. .

Abstract

Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

Keywords: DNA binding; inhibitors; oncogenes; protein/DNA interaction; protein/protein interaction; transcription factor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Targeting the MLL complex at the epigenetic level controls the expression of the HOXA cluster of transcription factors. Top of the figure: scheme of proteins associated with the fused-MLL complex highlighting the ones targeted by the different inhibitors indicated below.
Figure 2
Figure 2
CDK7 inhibitors for targeting MYC transcription factor promoter at the epigenetic level.
Figure 3
Figure 3
Small compounds (Top) or drug-linker peptides (Middle and Bottom) inducing degradation of oncogenic transcription factors.
Figure 4
Figure 4
Targeting transcription factor at the protein/protein interaction level. (A) p53/mdm2 PPIi; (B) Keap1/Nrf2 PPIi; (C) RUNX1/CBFβ PPIi; (D) Ets transcription factors/RNA helicase A PPIi; (E) STAT3 PPIi; (F) BCL6 PPIi.
Figure 5
Figure 5
Direct targeting of transcription factors. (A) PML-RARα; (B) Androgen receptor; (C) p53. (D) STAT3; (E) GLI1/2; (F) ETV1; (G) PAX2; (H) HSF1; (I) FOXM1.
Figure 6
Figure 6
DNA alkylating drugs as inhibitors of transcription factors/DNA binding.
Figure 7
Figure 7
DNA intercalating drugs as inhibitors of transcription factors/DNA binding.
Figure 8
Figure 8
Major groove DNA binding drugs as inhibitors of transcription factors/DNA binding.
Figure 9
Figure 9
Minor groove DNA binding drugs as inhibitors of transcription factors/DNA binding.
See this image and copyright information in PMC

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