Less than a decade ago, it was shown that bromodomains, acetyl lysine ‘reader’ modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein–protein or protein–peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.
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A.R.C. thanks colleagues at Constellation Pharmaceuticals for input and discussions about the manuscript.
A.G.C. is an employee of Genentech, R.J.S. was, and A.R.C. is, an employee of Constellation Pharmaceuticals. Constellation Pharmaceuticals has progressed a bromodomain and extra-terminal (BET) inhibitor into clinical trials.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
RCSB Protein Data Bank: https://www.rcsb.org/
- Phenotypic screening
Chemical compounds can be screened for a desired biological effect or phenotype (usually in cell culture) rather than screening for binding to, or inhibition of, a purified protein.
- Fragment-based ligand discovery
Fragments are low-molecular-weight chemical compounds that, although binding weakly to targets (with high micromolar to millimolar dissociation constants (Kd)), can be used to efficiently explore chemical space with a small compound collection.
- BET bromodomains
Bromodomain and extra-terminal (BET) family proteins include BRD2, BRD3, BRD4 and bromodomain testis-specific protein (BRDT). Each BET-family protein has two bromodomains (BD1 and BD2). BD1 and BD2 are highly similar to one another (therefore many drugs bind to both BD1 and BD2), and each is nearly identical across the BET family. BET inhibitors therefore bind to all four BET-family proteins, with any selectivity limited to the differences between BD1 and BD2.
Groups of small molecules related to one another by structure. Different chemotypes exhibiting the same expected mechanism of action (for example, bromodomain inhibition) are useful in establishing that cellular effects are likely caused by modulation of the intended target.
- NUT midline carcinoma
A rare but aggressive squamous cell carcinoma that results from chromosomal rearrangements of the gene encoding nuclear protein in testis (NUT), frequently resulting in fusion with BET proteins (BRD4–NUT or BRD3–NUT).
- Pleiotropic effects
A drug may modulate the intended target or may bind to an unrelated (and often unknown) target. Each of these can produce biological effects. One challenge in the use of chemical probes to learn about biology is separating on-target effects from any other effects.
- Positive transcription elongation factor b
(P-TEFb). Also known as the CDK9–cyclinT heterodimer, P-TEFb phosphorylates and activates RNA polymerase II. The BRD4 carboxy-terminal domain binds P-TEFb at promoters and enhancer regions.
- Proteolysis-targeting chimaera
(PROTAC). Bifunctional molecules that induce targeted protein degradation through co-opting the cellular ubiquitin machinery.
- Nucleosome core particle
This basic unit of chromatin is a histone protein octamer (two copies each of histones H2A, H2B, H3 and H4) wrapped twice by ~147 bp of DNA.
- NanoBRET assay
A cellular assay measuring the proximity of two proteins through bioluminescence resonance energy transfer (BRET), as developed by the Promega Corporation. For bromodomain (BD) research, the assay usually involves an expressed fusion of the luciferase variant nanoLuc to a histone protein. The BD protein is fused to the HaloTag protein. Cells are treated with a fluorescent ligand that covalently attaches to the expressed HaloTag protein. If the tagged BD binds to the histone, BRET occurs. Addition of a BD inhibitor reduces the BRET signal.
- Fluorescence recovery after photobleaching (FRAP) assay
A cellular assay in which laser-induced photobleaching of a fluorescent protein localized in an area of a cell results in a dark spot that can be repopulated by dynamically relocalizing fluorescent proteins. The half-time (t1/2) for recovery of fluorescence is a measure of how strongly localized the bulk population is. For example, a bromodomain (BD) binding to chromatin is less dynamic than an inhibitor-bound BD that is not bound to chromatin. The inhibitor will result in a reduced recovery t1/2 in a FRAP assay.
Substrates degraded by the cellular ubiquitin system are often recognized through sequence motifs (degrons) that may or may not include post-translational modifications regulating degradation.
- ‘Click’ chemistry
‘Click’ reactions are crosslinking chemistries that are both selective and sufficiently mild to be useful in complex biological samples.
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Cochran, A.G., Conery, A.R. & Sims, R.J. Bromodomains: a new target class for drug development. Nat Rev Drug Discov 18, 609–628 (2019). https://doi.org/10.1038/s41573-019-0030-7
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