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Structure–Activity Relationship Studies on ( R )‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7
Author(s) -
Lenstra Danny C.,
Damen Eddy,
Leenders Ruben G. G.,
Blaauw Richard H.,
Rutjes Floris P. J. T.,
Wegert Anita,
Mecinović Jasmin
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800242
Subject(s) - lysine , methyltransferase , acetylation , chemistry , histone , enzyme , biochemistry , stereochemistry , pharmacology , biology , methylation , amino acid , dna , gene
Abstract SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small‐molecule inhibitors have been reported that target SETD7, the most potent being ( R )‐PFI‐2. Herein we report structure–activity relationship studies on ( R )‐PFI‐2 and its analogues. A library of 29 structural analogues of ( R )‐PFI‐2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between ( R )‐PFI‐2′s NH 2 + group and SETD7′s Asp256 and His252 residue, respectively.