Design and synthesis of new non nucleoside inhibitors of DNMT3A.

Authors :: Erdmann A
Menon Y
Gros C
Molinier N
Novosad N
Samson A
Gregoire JM
Long C
Ausseil F
Halby L
Arimondo PB
Source :: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Sep 01; Vol. 23 (17), pp. 5946-53. Date of Electronic Publication: 2015 Jul 10.
Publication Year :: 2015
Abstract: DNA methylation, an epigenetic modification regulating gene expression, is a promising target in cancer. In an effort to identify new non nucleosidic inhibitors of DNA methyltransferases, the enzymes responsible for DNA methylation, we carried out a high-throughput screening of 66,000 chemical compounds based on an enzymatic assay against catalytic DNMT3A. A family of propiophenone derivatives was identified. After chemical optimization and structure activity relationship studies, a new inhibitor (33) was obtained with an EC50 of 2.1 μM against DNMT3A. The mechanism of inhibition of the compound was investigated as it forms a reactive Michael acceptor group in situ. Thereby, the Michael acceptor 20 was identified. This compound was further characterized for its biological activity in cancer cells.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)