Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer
Abstract
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi 1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice 6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions 7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported 10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment 10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075 14. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
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CDK9 inhibitor KB-0742 and BRD4 bromodomain 2 inhibitor ABBV-744 have shown high selectivity in transcriptional programs, making them attractive candidates for therapeutic development.
“CDK9 inhibitor KB-0742 and BRD4 bromodomain 2 (BD2) inhibitor ABBV-744 have shown high selectivity in transcriptional programs, making them attractive candidates for therapeutic development.623,624”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [624]
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- Authors
- Faivre, E. J., McDaniel, K. F., Albert, D. H., Mantena, S. R., Plotnik, J. P., Wilcox, D., Zhang, L., Bui, M. H., Sheppard, G. S., Wang, L., Sehgal, V., Lin, X., Huang, X., Lu, X., Uziel, T., Hessler, P., Lam, L. T., Bellin, R. J., Mehta, G., Fidanze, S., Pratt, J. K., Liu, D., Hasvold, L. A., Sun, C., Panchal, S. C., Nicolette, J. J., Fossey, S. L., Park, C. H., Longenecker, K., Bigelow, L., Torrent, M., Rosenberg, S. H., Kati, W. M., & Shen, Y.
- Affiliations
- AbbVie (United States) (US)
- Corresponding author
- Shen, Yu
- ORCID
- Venue
- Nature
- Published
- 2020-01-22
- Volume
- 578
- Issue
- 7794
- Pages
- 306-310
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3001038414
- Cited by
- 408
- References
- 29
- Citations by year
- 2026: 33 · 2025: 54 · 2024: 60 · 2023: 60 · 2022: 64 · 2021: 81 · 2020: 55
- FWCI
- 23.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- BET inhibitors, BRD4, prostate cancer, androgen receptor, super-enhancers, ABBV-075, thrombocytopenia, gastrointestinal toxicity, on-target toxicity, acute myeloid leukemia, histone acetylation, epigenetic reader protein, drug discovery
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Animals, Enhancer Elements, Genetic, Humans, Male, Prostatic Neoplasms, Pyridines, Pyrroles, Receptors, Androgen, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Rats
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