Structure–Activity Relationship Studies on ( R )‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7 | Zendy

Lenstra Danny C. | Zendy; Damen Eddy | Zendy; Leenders Ruben G. G. | Zendy; Blaauw Richard H. | Zendy; Rutjes Floris P. J. T. | Zendy; Wegert Anita | Zendy; Mecinović Jasmin | Zendy

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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

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.

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