Publication: 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
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Dolbois, A., Bedi, R. K., Bochenkova, E., Müller, A., Moroz-Omori, E. V., Huang, D., & Caflisch, A. (2021). 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors. Journal of Medicinal Chemistry, 64(17), 12738–12760. https://doi.org/10.1021/acs.jmedchem.1c00773
Abstract
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Abstract
N6-methyladenosine (m6A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m6A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC50 of 5 nM for the lead compound 22 (UZH2) in a time-resolv
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- Dolbois, Aymeric
- Bedi, Rajiv K
- Bochenkova, Elena
- Müller, Anna
- Moroz-Omori, Elena V
- Huang, Danzhi
- Caflisch, Amedeo
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Dolbois, A., Bedi, R. K., Bochenkova, E., Müller, A., Moroz-Omori, E. V., Huang, D., & Caflisch, A. (2021). 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors. Journal of Medicinal Chemistry, 64(17), 12738–12760. https://doi.org/10.1021/acs.jmedchem.1c00773
