Targeting transcription factors in cancer — from undruggable to reality

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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.

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Fig. 1: Targeting transcription factor drivers in cancer.
Fig. 2: Targeting oestrogen receptor function.
Fig. 3: Examples of protein–protein interaction inhibitors targeting transcription factors.
Fig. 4: Approaches to modulate transcription factor stability by way of regulating ubiquitylation.
Fig. 5: The mechanism of action of a proteolysis targeting chimaera.

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Acknowledgements

The author thanks the many outstanding trainees in the laboratory over the years who facilitated the work and whose many stimulating discussions guided the composition of this Review, and D. Brautigan at University of Virginia, USA, for helping produce a readable meaningful scientific review. Apologies to those whose important contributions have not been highlighted owing to space limitations.

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Correspondence to John H. Bushweller.

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J.H.B. has a licensing agreement with Systems Oncology for the CBFβ–SMMHC inhibitor AI-10-49 (LeuSO).

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Nature Reviews Cancer thanks A. Koehler, D. Tenen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Hotspot residues

Specific amino acids on a protein–protein interaction surface that contribute the most energy to the binding of the two proteins.

Interaction energy

The energy, typically measured in kilocalories per mole, associated with the binding of two species to one another (protein–protein, protein–nucleic acid, protein–small molecule).

Allosteric modulation

Acting by binding at a site distinct from the primary site of activity of a protein, for example, at a site distinct from the active site of an enzyme.

Epigenetic reader

A protein that binds to peptide elements, typically from histones or transcription factors, that have specific post-translational modifications, for example, methylation, acetylation or phosphorylation.

Epigenetic writer

A protein that adds specific post-translational modifications, including methylation and acetylation, to peptide elements in histones and transcription factors.

Bioavailability

The proportion of a drug that enters the circulation after administration and can have an active effect.

Castration-resistant prostate cancer

(CRPC). Prostate cancer that progresses despite androgen depletion therapy.

Absorption, distribution, metabolism, excretion, toxicity

(ADMET). Important properties of drugs that determine their efficacy.

Definitive haematopoiesis

Blood cell development involving haematopoietic stem cells that differentiate to produce all of the lineages of the haematopoietic system. In contrast to primitive (embryonic) haematopoiesis, this process occurs later in development.

Nuclear magnetic resonance (NMR) spectroscopy

A technique that relies on energy differences of nuclear spins in a magnetic field that is used for determining protein 3D structure, protein dynamics and drug binding to proteins

Deubiquitinases

(DUBs). Enzymes that remove ubiquitin from proteins.

Michael acceptor

A chemical moiety that can react with amino acid side chains in a protein to form a covalent bond with the protein

K d

The equilibrium dissociation constant, a measure of the affinity of binding of two molecules to one another.

DNA minor groove

Along with the major groove, the minor groove makes up the 3D structure of DNA and provides contacts to bind proteins or small molecules.

Chemoproteomics

The use of proteomics approaches, typically based on functionalized chemical probes in conjunction with mass spectrometry, to identify the targets of action of molecules in cells.

pK a

The negative log of the equilibrium association constant, used for characterizing the acidity of exchangeable protons on the side chains of amino acids in proteins.

X-ray crystallography

A technique that utilizes the diffraction of X-rays to determine the 3D structure of proteins and nucleic acids.

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