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Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2
Open accessAbstract
Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity, (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide). The compound induces apoptosis and differentiation specifically in SMARCB1 -deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.
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Cites
The Polycomb complex PRC2 and its mark in life
Margueron, R., & Reinberg, D. (2011) · Nature · doi:10.1038/nature09784 · Cited by 3,347
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells
Knutson, S. K., Wigle, T. J., Warholic, N. M., Sneeringer, C. J., Allain, C. J., Klaus, C. R., Sacks, J. D., Raimondi, A., Majer, C. R., Song, J., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1084 · Cited by 776
Self-citation
Cited by
Kim, K. H., & Roberts, C. W. M. (2016) · Nature Medicine · doi:10.1038/nm.4036 · Cited by 1,471
Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers
Bitler, B. G., Aird, K. M., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A. V., Schultz, D. C., Liu, Q., Shih, I.-M., Conejo-Garcia, J. R., et al. (2015) · Nature Medicine · doi:10.1038/nm.3799 · Cited by 678
Ajani, J. A., Lee, J., Sano, T., Janjigian, Y. Y., Fan, D., & Song, S. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.36 · Cited by 594
EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
Mohammad, F., Weissmann, S., Leblanc, B., Pandey, D. P., Højfeldt, J. W., Comet, I., Zheng, C., Johansen, J. V., Rapin, N., Porse, B. T., et al. (2017) · Nature Medicine · doi:10.1038/nm.4293 · Cited by 535
Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy
Lu, Y., Chan, Y.-T., Tan, H.-Y., Li, S., Wang, N., & Feng, Y. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01197-3 · Cited by 499
Metadata
- Authors
- Knutson, S. K., Warholic, N. M., Wigle, T. J., Klaus, C. R., Allain, C. J., Raimondi, A., Porter Scott, M., Chesworth, R., Moyer, M. P., Copeland, R. A., Richon, V. M., Pollock, R. M., Kuntz, K. W., & Keilhack, H.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2013-04-25
- Volume
- 110
- Issue
- 19
- Pages
- 7922-7927
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2132310381
- Cited by
- 789
- References
- 2
- FWCI
- 25.69
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Knutson, S. K., Warholic, N. M., Wigle, T. J., Klaus, C. R., Allain, C. J., Raimondi, A., Porter Scott, M., Chesworth, R., Moyer, M. P., Copeland, R. A., Richon, V. M., Pollock, R. M., Kuntz, K. W., & Keilhack, H. (2013). Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1303800110
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