Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours
Open accessAbstract
The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.
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P300 inhibitor directly inhibits AR transcriptional activity and H3K27ac deposition at ARE site.
“P300 inhibitor directly inhibits AR transcriptional activity and H3K27ac deposition at the ARE site (Lasko et al., 2017).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Lasko et al., 2017
The paper reports that A-485 attenuated AR-dependent gene expression and reduced H3K27Ac at the androgen response element of the PSA enhancer. It describes direct inhibition of AR transcriptional activity as a suggestion from the timing of those effects, rather than an established finding; the claim omits that uncertainty. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAR positive prostate cancer cells are particularly sensitive to p300 inhibitors compared to other solid tumor cells.
“It has been reported that AR positive prostate cancer cells are particularly sensitive to p300 inhibitors comparing to other solid tumor cells (Lasko et al., 2017).”
From Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes (2020) · cites this paper as Lasko et al., 2017
The relationship between TF occupancy and gene expression can be well fit by modifying the telegraph model to include a promoter on-rate proportional to the average number of TFs bound (Additive Activation model).
“This relationship between TF occupancy and gene expression can be well fit by modifying the commonly-used “telegraph” model of transcription31–33, which assumes that promoters can be either “on” (transcribing) or “off”, to include a promoter on-rate that is proportional to the average number of TFs bound (Additive Activation model; Fig. 3F, Methods)”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [32]
The passages on gene-expression profiling discuss the effects of the p300/CBP inhibitor A-485, not a model relating transcription-factor occupancy to expression (section labelled Abstract; page unavailable). Searches for the telegraph model, Additive Activation, and a promoter on-rate proportional to bound transcription factors found no passage addressing that claim. (LLM, conf=0.76)
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References 23 · Cited by 858
- Authors
- Lasko, L. M., Jakob, C. G., Edalji, R. P., Qiu, W., Montgomery, D., Digiammarino, E. L., Hansen, T. M., Risi, R. M., Frey, R., Manaves, V., Shaw, B., Algire, M., Hessler, P., Lam, L. T., Uziel, T., Faivre, E., Ferguson, D., Buchanan, F. G., Martin, R. L., Torrent, M., Chiang, G. G., Karukurichi, K., Langston, J. W., Weinert, B. T., Choudhary, C., de Vries, P., Kluge, A. F., Patane, M. A., Van Drie, J. H., Wang, C., McElligott, D., Kesicki, E., Marmorstein, R., Sun, C., Cole, P. A., Rosenberg, S. H., Michaelides, M. R., Lai, A., & Bromberg, K. D.
- Affiliations
- AbbVie (United States) (US)
- University of Copenhagen (DK)
- Novartis (China) (CN)
- University of Pennsylvania (US)
- Johns Hopkins University (US)
- Corresponding author
- Lai, Albert
- Bromberg, Kenneth D.
- ORCID
- Venue
- Nature
- Published
- 2017-09-27
- Volume
- 550
- Issue
- 7674
- Pages
- 128-132
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6050590
- OpenAlex
- W2758743773
- Cited by
- 858
- References
- 23
- Citations by year
- 2026: 114 · 2025: 135 · 2024: 141 · 2023: 76 · 2022: 73 · 2021: 111 · 2020: 98 · 2019: 63 · 2018: 40 · 2017: 6
- FWCI
- 24.25
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-05-16)
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF14OC0008541)
- National Institute of General Medical Sciences (R37GM062437)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- P300, CREB-binding protein, histone acetyltransferase inhibitors, A-485, co-crystal structure, hematologic malignancies, androgen receptor-positive prostate cancer, castration-resistant prostate cancer, transcriptional coactivator, small molecule inhibitors
- MeSH terms
- Acetyl Coenzyme A, Animals, Antineoplastic Agents, Binding, Competitive, Enzyme Inhibitors, Heterocyclic Compounds, 4 or More Rings, Humans, Male, Models, Molecular, Neoplasms, Protein Conformation, Receptors, Androgen, Gene Expression Regulation, Neoplastic, Mice, SCID, Crystallography, X-Ray, Cell Lineage, Hematologic Neoplasms, Catalytic Domain, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, p300-CBP Transcription Factors, Mice, Histone Acetyltransferases, Biocatalysis, Prostatic Neoplasms, Castration-Resistant
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