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Review
, 14 (3), 331-40

A Complex Task? Direct Modulation of Transcription Factors With Small Molecules

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Review

A Complex Task? Direct Modulation of Transcription Factors With Small Molecules

Angela N Koehler. Curr Opin Chem Biol.

Abstract

Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein-protein or protein-DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be 'undruggable.' This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.

Figures

Figure 1
Figure 1
Novel modulators of nuclear receptors. (a) Recently discovered ligands for HNFα include endogenous linoleic acid and synthetic nitronapthofuran compound 5. (b) Coactivator binding inhibitors that target TR-SRC (β-aminoketone 17{3,3,4}), ER-SRC (guanylhydrazone 23, amphipathic benzene 3c, 6-alkyldiaminopyrimidine 18b), and AR-SRC interactions (AR-selective diaminopyrimidine 14).
Figure 2
Figure 2
Small-molecule modulators of resident nuclear factors. (a) Selected small-molecule inhibitors of c-Myc function, including inhibitors of c-Myc/Max heterodimer formation and c-Myc/Max DNA binding. (b) Small-molecule modulators of HOXA13 (lactam carboxamide 31), E2F (HLM006474), and CBFB-RUNX2 (2-aminothiazole 17).
Figure 3
Figure 3
Representative small-molecule modulators of latent cytoplasmic transcription factors. (a) Direct STAT modulators (b) Direct modulators of HIF-1 or p300/CBP (c) Modulator of NME2.
Figure 4
Figure 4
Targeting the oncogenic EWS-FLI1 transcription factor translocation product with small molecules. (a) Schematic representation of the EWS-FLI1 fusion protein resulting from the t(22;11) translocation. The RNA binding domain (RBD), ETS DNA binding domains (DBD), and transactivation domains (TAD) are indicated. The fusion gene can vary depending on whether exons 5–9 or 6–9 of FLI1 are involved. (b) Small molecules that disrupt the EWS-FLI1 interaction with RNA helicase A.

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