Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins

  • Eur J Med Chem. 2019 Nov 15;182:111633. doi: 10.1016/j.ejmech.2019.111633.
Deheng Chen  1 ,  Tian Lu  2 ,  Ziqin Yan  3 ,  Wenchao Lu  1 ,  Feilong Zhou  3 ,  Xilin Lyu  3 ,  Biling Xu  4 ,  Hualiang Jiang  3 ,  Kaixian Chen  2 ,  Cheng Luo  5 ,  Yujun Zhao  6
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China.
  • 4. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; School of Life Science and Medicine, Dalian University of Technology, 2 Dagong Road, Panjin, China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 31461688 DOI: 10.1016/j.ejmech.2019.111633
Abstract

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 Inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

Keywords
BD2; BET protein; Bromodomain; Crystal structure; Selective.
Products