Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor
Open accessAbstract
The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.
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A small-molecule ligand binds with low-nanomolar affinity to the bromodomain of TRIM24, and a crystal structure shows the inhibitor deeply inserted into the acetyl-lysine binding pocket.
“a small-molecule ligand can bind with low-nanomolar affinity to the bromodomain of TRIM24, and a crystal structure shows that the inhibitor is deeply inserted into the acetyl-lysine binding pocket of the bromodomain 129”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [129]
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- Authors
- Palmer, W. S., Poncet-Montange, G., Liu, G., Petrocchi, A., Reyna, N., Subramanian, G., Theroff, J., Yau, A., Kost-Alimova, M., Bardenhagen, J. P., Leo, E., Shepard, H. E., Tieu, T. N., Shi, X., Zhan, Y., Zhao, S., Barton, M. C., Draetta, G., Toniatti, C., Jones, P., Geck Do, M., & Andersen, J. N.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Palmer, Wylie S.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-07-06
- Volume
- 59
- Issue
- 4
- Pages
- 1440-1454
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC4755933
- OpenAlex
- W2262681364
- Cited by
- 168
- References
- 46
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 17 · 2020: 9 · 2019: 18 · 2018: 9 · 2017: 14 · 2016: 22 · 2015: 8
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of Texas MD Anderson Cancer Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- TRIM24, BRPF1, bromodomain inhibitors, structure-based drug design, histone acetyltransferase complexes, epigenetic regulation, chemical probes, co-crystal structure, binding mode
- MeSH terms
- Bromodomain Containing Proteins, Animals, Benzimidazoles, Carrier Proteins, DNA-Binding Proteins, Female, Humans, Methylation, Nuclear Proteins, Protein Binding, Drug Design, Adaptor Proteins, Signal Transducing, Mice, Molecular Docking Simulation
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