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Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase
- Source :
- Journal of medicinal chemistry. 62(17)
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Models, Molecular
S-Adenosylmethionine
Methyltransferase
Lysine
01 natural sciences
Small Molecule Libraries
03 medical and health sciences
Structure-Activity Relationship
Drug Discovery
Structure–activity relationship
Humans
Binding site
Enzyme Inhibitors
Enhancer
Cells, Cultured
030304 developmental biology
Cell Proliferation
chemistry.chemical_classification
0303 health sciences
Binding Sites
Dose-Response Relationship, Drug
Molecular Structure
Substrate (chemistry)
Histone-Lysine N-Methyltransferase
Small molecule
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Enzyme
chemistry
Biochemistry
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 62
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....e491e646b8409403d237931a50d510f6