Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7 |
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| Authors: | Danny C Lenstra Dr Eddy Damen Dr Ruben G G Leenders Dr Richard H Blaauw Prof?Dr Floris P J T Rutjes Dr Anita Wegert Dr Jasmin Mecinovi? |
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| Affiliation: | 1. Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands;2. Mercachem BV, Nijmegen, The Netherlands;3. Chiralix, Nijmegen, The Netherlands |
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| 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 NH2+ group and SETD7′s Asp256 and His252 residue, respectively. |
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| Keywords: | (R)-PFI-2 epigenetics histone lysine methyltransferase SETD7 structure– activity relationships |
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