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Advances in targeting ‘undruggable’ transcription factors with small molecules

Nature Reviews Drug Discovery volume 20, pages 669–688 (2021)Cite this article

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Abstract

Transcription factors (TFs) represent key biological players in diseases including cancer, autoimmunity, diabetes and cardiovascular disease. However, outside nuclear receptors, TFs have traditionally been considered ‘undruggable’ by small-molecule ligands due to significant structural disorder and lack of defined small-molecule binding pockets. Renewed interest in the field has been ignited by significant progress in chemical biology approaches to ligand discovery and optimization, especially the advent of targeted protein degradation approaches, along with increasing appreciation of the critical role a limited number of collaborators play in the regulation of key TF effector genes. Here, we review current understanding of TF-mediated gene regulation, discuss successful targeting strategies and highlight ongoing challenges and emerging approaches to address them.

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Fig. 1: Anatomy of a TF.
Fig. 2: Overview of the modern model of the transcriptional activation process.
Fig. 3: Common mechanisms of transcriptional dysregulation in disease.
Fig. 4: Examples of molecules that target TFs by various mechanisms.
Fig. 5: Overview of monomeric and PROTAC-based targeted protein degradation strategies.

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Acknowledgements

The authors acknowledge funding received from the National Institutes of Health (NIH) (U54CA231630-01A1) and the Emerson Collective.

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Authors and Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Madeleine J. Henley & Angela N. Koehler

  2. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Madeleine J. Henley & Angela N. Koehler

  3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Madeleine J. Henley & Angela N. Koehler

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Glossary

Non-specific TF binding sites

Sequences of DNA that do not contain the consensus sequence for a transcription factor (TF) DNA-binding domain (DBD). Most DBDs have low affinity for non-specific sites, but because of the exceptionally high ratio of non-specific to specific sites, TFs often spend significant time at non-specific sites.

Specific TF binding sites

Sequences of DNA that contain the consensus sequence for a transcription factor (TF) DNA-binding domain.

Transcriptional condensates

Liquid–liquid phase-separated droplets containing transcription factors, co-activators, RNA polymerase II (Pol II) and other transcriptional machinery.

Pre-initiation complex

A large complex comprising general transcription factors, Mediator and other proteins that position and activate RNA polymerase II (Pol II) at the transcription start site.

Cooperativity

In transcription, a phenomenon where binding of one transcription factor and/or co-regulator at a regulatory element enhances the binding of other factors, and vice versa.

Core regulatory TFs

(Also known as master TFs). Self-regulated transcription factors (TFs) that control cell identity and fate.

Chromatin readers

Proteins, such as bromodomains, that bind to post-translationally modified histones.

Ubiquitin–proteasome system

A system of intracellular protein degradation that is mediated by transfer of ubiquitin to target proteins by ubiquitin E3 ligases to mark them for degradation by the proteasome.

Molecular glues

Small molecules that directly mediate a non-native protein–protein interaction.

Histone deacetylases

(HDACs). Enzymes that remove acetyl groups from acetylated Lys residues in histones. Generally associated with closed chromatin conformation and transcriptional repression.

Histone acetyltransferases

(HATs). Enzymes that transfer acetyl groups to the ε-amino group of Lys residues in histones. Generally associated with open chromatin conformation and increased transcription.

Chromatin remodellers

Protein complexes with a common ATPase domain that use ATP hydrolysis to move, reposition or eject nucleosomes.

Intrinsically disordered proteins

(IDPs; also known as intrinsically disordered regions (IDRs)). Proteins or regions of proteins that do not adopt a well-defined structure. Often characterized as ‘ensembles’ of many unrelated protein conformations, although many IDPs/IDRs can transiently form more defined structures.

NMR spectroscopy

A structural technique that utilizes the quantum-mechanical properties of nuclear spins in a magnetic field. Used in structural biology to determine protein structure, as well as to characterize conformational dynamics across a wide range of timescales (general range of picoseconds to hours/days).

Molecular dynamics

A computational technique that is used to characterize the structure and conformational dynamics of proteins by simulating the interactions between all the atoms of a protein and its surrounding solvent over time.

Occupancy-based modulators

Modulators of protein function in drug discovery where the overall change in protein activity from drug treatment is determined by the concentration of the drug in the cell and its affinity for its target. For complete inhibition of activity by an inhibitor, the drug must reach concentrations several times above its dissociation constant (Kd).

ARV7

A splice variant of the androgen receptor that lacks the ligand-binding domain.

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Henley, M.J., Koehler, A.N. Advances in targeting ‘undruggable’ transcription factors with small molecules. Nat Rev Drug Discov 20, 669–688 (2021). https://doi.org/10.1038/s41573-021-00199-0

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