Structural Basis of Substrate Methylation and Inhibition of SMYD2
Open accessAbstract
Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
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AZ505 is a selective SMYD2 inhibitor with an IC50 of 0.12 μM and greater than 600-fold selectivity.
“We used AZ505, a selective SMYD2 inhibitor with an IC50 of 0.12 μM41 (>600 fold selectivity).”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [41]
The HTS Assay and Hit Validation section reports AZ505’s IC50 as 0.12 (rendered as “mM” in our copy), and the Cofactor Binding Site section reports no potency against SMYD3. The paper describes a selectivity profile, but the passages do not establish the claimed greater-than-600-fold figure. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBecause AZ505 binds to the active center of SMYD2, these experiments showed that SMYD2 enzymatic activity, and not just protein levels, contributes to fatty liver phenotypes.
“Because AZ505 binds to the active center of SMYD241, these experiments also showed that SMYD2 enzymatic activity, and not just protein levels, contributes to fatty liver phenotypes.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [41]
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Cites
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Epigenetic protein families: a new frontier for drug discovery
Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., & Schapira, M. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3674 · Cited by 1,327 · see citing works
Critical roles of non-histone protein lysine methylation in human tumorigenesis
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- Authors
- Ferguson, A. D., Larsen, N. A., Howard, T., Pollard, H., Green, I., Grande, C., Cheung, T., Garcia-Arenas, R., Cowen, S., Wu, J., Godin, R., Chen, H., & Keen, N.
- Affiliations
- AstraZeneca (United States) (US)
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Ferguson, Andrew D.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 19
- Issue
- 9
- Pages
- 1262-1273
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2071407989
- Cited by
- 203
- References
- 1
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 10 · 2021: 13 · 2020: 6 · 2019: 17 · 2018: 14 · 2017: 14 · 2016: 18 · 2015: 14 · 2014: 19 · 2013: 22 · 2012: 15
- FWCI
- 8.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- SMYD2, lysine methyltransferase, p53, Rb, crystal structure, peptide binding groove, oncoprotein, therapeutic target, epigenetic regulation
- MeSH terms
- Antineoplastic Agents, Binding Sites, Coenzymes, Drug Screening Assays, Antitumor, Esophageal Neoplasms, Humans, Hydrogen Bonding, Methylation, Models, Molecular, Peptide Fragments, Protein Binding, Histone-Lysine N-Methyltransferase, Surface Properties, beta-Alanine, Tumor Suppressor Protein p53, Crystallography, X-Ray, Catalytic Domain, Amino Acid Motifs, Benzoxazines, Enzyme Assays, High-Throughput Screening Assays, Hydrophobic and Hydrophilic Interactions
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