Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor
Open accessAbstract
SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies.
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EPZ031686 binds in the lysine substrate binding pocket of SMYD3 and noncompetitively with SAM.
“Structural studies have shown that EPZ031686 binds in the lysine substrate binding pocket of SMYD3 and noncompetitively with SAM29.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [29]
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Copeland, R. A. (2005) · PubMed · Cited by 1,045 · see citing works
Self-citationSMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells
Hamamoto, R., Furukawa, Y., Morita, M., Iimura, Y., Pittella-Silva, F., Li, M., Yagyu, R., & Nakamura, Y. (2004) · Nature Cell Biology · doi:10.1038/ncb1151 · Cited by 738 · see citing works
Evaluation of Enzyme Inhibitors in Drug Discovery
Copeland, R. A. (2013) · Wiley eBooks · doi:10.1002/9781118540398 · Cited by 689 · see citing works
Self-citationSMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer
Mazur, P., Reynoird, N., Khatri, P., Jansen, P., Wilkinson, A. W., Liu, S.-C., Barbash, O., Aller, G. V. V., Huddleston, M. J., Dhanak, D., et al. (2014) · Nature · doi:10.1038/nature13320 · Cited by 370 · see citing works
Enhanced SMYD3 expression is essential for the growth of breast cancer cells
Hamamoto, R., Pittella-Silva, F., Tsuge, M., Nishidate, T., Katagiri, T., Nakamura, Y., & Furukawa, Y. (2006) · Cancer Science · doi:10.1111/j.1349-7006.2006.00146.x · Cited by 275 · see citing works
Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation
Aller, G. S. V., Reynoird, N., Barbash, O., Huddleston, M. J., Liu, S., Zmoos, A., McDevitt, P. J., Sinnamon, R. H., Le, B., Martín, G. M., et al. (2012) · Epigenetics · doi:10.4161/epi.19506 · Cited by 174 · see citing works
Deregulated expression of selected histone methylases and demethylases in prostate carcinoma
Vieira, F. Q., Costa‐Pinheiro, P., Ramalho-Carvalho, J., Faria‐Pereira, A., Menezes, F. D., Antunes, L., Carneiro, I. C., Oliveira, J., Henrique, R., & Jerónimo, C. (2013) · Endocrine Related Cancer · doi:10.1530/erc-13-0375 · Cited by 103 · see citing works
Vieira, F. Q., Costa‐Pinheiro, P., Almeida-Rios, D., Graça, I. C. R., Monteiro‐Reis, S., Simoes‐Sousa, S., Carneiro, I. C., Sousa, E., Godinho, M. I., Baltazar, F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3767 · Cited by 77 · see citing works
SMYD3 as an Oncogenic Driver in Prostate Cancer by Stimulation of Androgen Receptor Transcription
Liu, C., Wang, C., Wang, K., et al. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt304 · Cited by 77 · see citing works
Liu, Y., Liu, H., Luo, X., et al. (2015) · Tumor Biology · doi:10.1007/s13277-015-3077-z · Cited by 71 · see citing works
Sponziello, M., Durante, C., Boichard, A., Dima, M., Puppin, C., Verrienti, A., Tamburrano, G., Rocco, G. D., Redler, A., Lacroix, L., et al. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.04.016 · Cited by 64 · see citing works
Pittella-Silva, F., Hamamoto, R., Kunizaki, M., Tsuge, M., Nakamura, Y., & Furukawa, Y. (2007) · Oncogene · doi:10.1038/sj.onc.1210929 · Cited by 59 · see citing works
Overexpression of SMYD3 was associated with increased STAT3 activation in gastric cancer
Liu, Y., Deng, J., Luo, X., et al. (2014) · Medical Oncology · doi:10.1007/s12032-014-0404-y · Cited by 36 · see citing works
SMYD3 overexpression was a risk factor in the biological behavior and prognosis of gastric carcinoma
Liu, Y., Luo, X., Deng, J., et al. (2014) · Tumor Biology · doi:10.1007/s13277-014-2891-z · Cited by 33 · see citing works
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Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
Wang, Y., Dix, M. M., Bianco, G., Remsberg, J. R., Lee, H.-Y., Kalocsay, M., Gygi, S. P., Forli, S., Vite, G., Lawrence, R. M., et al. (2019) · Nature Chemistry · doi:10.1038/s41557-019-0351-5 · Cited by 179 · see citing works
- Authors
- Mitchell, L. H., Boriack-Sjodin, P. A., Smith, S., Thomenius, M., Rioux, N., Munchhof, M., Mills, J. E., Klaus, C., Totman, J., Riera, T. V., Raimondi, A., Jacques, S. L., West, K., Foley, M., Waters, N. J., Kuntz, K. W., Wigle, T. J., Scott, M. P., Copeland, R. A., Smith, J. J., & Chesworth, R.
- Affiliations
- Epizyme (United States) (US)
- Epizyme Inc., Fourth Floor, 400 Technology Square, Cambridge, Massachusetts 02139, United States
- Corresponding author
- Mitchell, Lorna H.
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-08-28
- Volume
- 7
- Issue
- 2
- Pages
- 134-138
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC4753551
- OpenAlex
- W2287573955
- Cited by
- 91
- References
- 14
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 15 · 2018: 7 · 2017: 5 · 2016: 13 · 2015: 2
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- SMYD3, histone methyltransferase inhibitors, small molecule inhibitors, oral bioavailability, target validation
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