| Autor: |
Taylor, Alexandria P., Swewczyk, Magdalena, Kennedy, Steven, Trush, Viacheslav V., Wu, Hong, Zeng, Hong, Dong, Aiping, Ferreira de Freitas, Renato, Tatlock, John, Kumpf, Robert A., Wythes, Martin, Casimiro-Garcia, Agustin, Denny, Rajiah Aldrin, Parikh, Mihir D., Li, Fengling, Barsyte-Lovejoy, Dalia, Schapira, Matthieu, Vedadi, Masoud, Brown, Peter J., Arrowsmith, Cheryl H., Owen, Dafydd R. |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3−9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting point for a selective, cell-active inhibitor given its extreme physicochemical properties and its role in multiple cellular processes. A previously untested medicinal chemistry strategy of deliberate file enrichment around molecules bearing the hallmarks of SAM, but with improved lead-like properties from the outset, yielded viable hits against SET and MYND domain-containing protein 2 (SMYD2) that were shown to bind in the co-factor site. These leads were optimized to identify a highly biochemically potent, PKMT-selective, and cell-active chemical probe. While substrate-based inhibitors of PKMTs are known, this represents a novel, co-factor-derived strategy for the inhibition of SMYD2 which may also prove applicable to lysine methyltransferase family members previously thought of as intractable. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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