Targeting epigenetic reader and eraser: Rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors
- Bioorg Med Chem Lett. 2016 Jun 15;26(12):2931-2935. doi: 10.1016/j.bmcl.2016.04.034.
- 1. Department of Organic Chemistry, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
- 2. Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China.
- 3. Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: [email protected].
- 4. Laboratory of Molecular Design and Drug Discovery, School of Science, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: [email protected].
The bromodomain protein module and histone deacetylase (HDAC), which recognize and remove acetylated lysine, respectively, have emerged as important epigenetic therapeutic targets in Cancer treatments. Herein we presented a novel design approach for Cancer drug development by combination of bromodomain and HDAC inhibitory activity in one molecule. The designed compounds were synthesized which showed inhibitory activity against bromodomain 4 and HDAC1. The representative dual bromodomain/HDAC inhibitors, compound 11 and 12, showed potent antiproliferative activities against human leukaemia cell line K562 and MV4-11 in cellular assays. This work may lay the foundation for developing dual bromodomain/HDAC inhibitors as potential Anticancer therapeutics.