Targeting transcription factors in cancer - from undruggable to reality

Abstract

Mutated or dysregulated transcription factors represent a unique class of drug targets that mediate aberrant gene expression, including blockade of differentiation and cell death gene expression programmes, hallmark properties of cancers. Transcription factor activity is altered in numerous cancer types via various direct mechanisms including chromosomal translocations, gene amplification or deletion, point mutations and alteration of expression, as well as indirectly through non-coding DNA mutations that affect transcription factor binding. Multiple approaches to target transcription factor activity have been demonstrated, preclinically and, in some cases, clinically, including inhibition of transcription factor-cofactor protein-protein interactions, inhibition of transcription factor-DNA binding and modulation of levels of transcription factor activity by altering levels of ubiquitylation and subsequent proteasome degradation or by inhibition of regulators of transcription factor expression. In addition, several new approaches to targeting transcription factors have recently emerged including modulation of auto-inhibition, proteolysis targeting chimaeras (PROTACs), use of cysteine reactive inhibitors, targeting intrinsically disordered regions of transcription factors and combinations of transcription factor inhibitors with kinase inhibitors to block the development of resistance. These innovations in drug development hold great promise to yield agents with unique properties that are likely to impact future cancer treatment.

Fig. 1 |. Targeting transcription factor drivers in cancer.

Schematic showing possible beneficial outcomes of inhibiting the activity of transcription factor drivers in cancer. EMT, epithelial-to-mesenchymal transition.

Fig. 2 |. Targeting oestrogen receptor function.

Schematic showing the regulation of gene expression by the nuclear hormone receptor oestrogen receptor (ER) and by small-molecule modulators of ER function. a | The oestrogen steroid hormone oestradiol binds to the ligand binding domain (LBD) of the ER to induce a conformational change that facilitates co-activator recruitment and activation of gene expression. b | Binding of a selective oestrogen receptor modulator (SERM) to the LBD blocks co-activator recruitment and thereby blocks gene activation. c | Binding of a selective oestrogen receptor degrader (SERD) promotes proteasome-mediated degradation of the ER, thereby blocking gene activation. DBD, DNA binding domain.

Fig. 3 |. Examples of protein–protein interaction inhibitors targeting transcription factors.

a | Core binding factor β (CBFβ) is a component of the CBF family of transcription factors that heterodimerizes with the runt-related transcription factor (RUNX) family of DNA binding proteins. CBFβ binding to RUNX1 enhances its binding to DNA and protects it from degradation. The CBFβ–smooth muscle myosin heavy chain (SMMHC) fusion protein associated with acute myeloid leukaemia retains the ability to bind RUNX1 through the CBFβ containing N-terminal portion of the fusion protein. The protein–protein interaction inhibitor AI-10-49 binds selectively to the CBFβ–SMMHC fusion to release RUNX1 and allow it to bind to its cognate sites in the genome and alter the gene expression programme. The inhibitor has two CBFβ binding moieties to make a bivalent interaction with the oligomeric CBFβ–SMMHC and achieve specificity for CBFβ–SMMHC versus wild-type CBFβ, which is monomeric in solution. b | MI-538 and subsequent derivatives bind to menin, a transcriptional co-activator that retains the ability to bind to the mixed lineage leukaemia (MLL) portion of MLL fusion proteins that arise in leukaemia (such as MLL–AF9, MLL–ENL and MLL–AF4). As a consequence, these protein–protein interaction inhibitors disrupt the binding of MLL fusions to specific sites in the genome, reducing expression of key MLL fusion target genes. CEBPA, CCAAT/enhancer binding protein α; CSF1R, colony-stimulating factor 1 receptor.

Fig. 4 |. Approaches to modulate transcription factor stability by way of regulating ubiquitylation.

a | Enhanced transcription factor (TF) degradation by small-molecule-promoted E3 ubiquitin ligase binding, leading to ubiquitylation and proteasome-dependent destruction of the protein of interest. For example, thalidomide and its derivatives that inhibit the growth of multiple myeloma cells do so by binding to a specific pocket in the E3 ubiquitin ligase cereblon (CRBN), enhancing CRBN interaction with the Ikaros family proteins IKZF1 and IKZF3, key drivers of multiple myeloma, and enhancing their ubiquitylation. b | Enhanced TF degradation by small-molecule inhibition of a deubiquitinase (DUB) specific for that TF, leading to higher levels of ubiquitylation and enhanced proteasomal degradation. For example, the DUB ubiquitin-specific-processing protease 9X (USP9X) deubiquitylates the transcription factor ETS-related gene (ERG), a critical driver of prostate cancer. Treatment with the USP9X inhibitor WP1130 leads to enhanced ubiquitylation and proteasomal destruction of ERG. c | Reduced TF degradation by small-molecule disruption of E3 ubiquitin ligase binding, leading to reduced ubiquitylation and reduced proteasomal degradation. For transcription factors that act as tumour suppressors, increasing their protein level via this approach could have therapeutic value. Ub, ubiquitin; VHL, von-Hippel Lindau.

Fig. 5 |. The mechanism of action of a proteolysis targeting chimaera.

This schematic illustrates the mode of action of a proteolysis targeting chimaera (PROTAC) targeting the epigenetic reader bromodomain-containing protein 4 (BRD4). PROTACs are bifunctional small molecules that interact with the protein of interest while simultaneously engaging an E3 ubiquitin ligase, effectively hijacking the cellular protein quality control machinery to selectively degrade the target protein. The PROTAC shown contains a ligand derived from thalidomide (blue square) for recruiting the E3 ubiquitin ligase cereblon (CRBN), a linker and another ligand (green circle) to bind to the bromodomain of BRD4. Once the BRD4–PROTAC–E3 ubiquitin ligase complex is formed, E2 ubiquitin-conjugating enzymes transfer ubiquitin (Ub) to lysine residues on the surface of BRD4. Consequently, the recognition of the lysine polyubiquitylation signal by the proteasome facilitates the degradation of BRD4. As the PROTAC can bind to one BRD4 protein and mediate its ubiquitylation, and then dissociate and bind to another BRD4 protein, the small molecule acts as a catalyst for ubiquitylation of BRD4 (indicated by the dashed arrow).