2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors

Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors

  • Bioorg Med Chem. 2019 Jul 1;27(13):2813-2821. doi: 10.1016/j.bmc.2019.05.006.
Xinzhou Bi 1,  Jieming Li 1,  Jiuhui Li 1,  Wei Shi 1,  Yuxuan Dai 1,  Qifei Li 1,  Wenjie Zhang 1,  Wenlong Huang 2,  Hai Qian 3,  Cheng Jiang 4
Affiliations

Affiliations

  • 1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jc@cpu.edu.cn.
PMID: 31079968 DOI: 10.1016/j.bmc.2019.05.006
Abstract

Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 μM. Cell Apoptosis and western blotting indicated compound 23 induced Apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.

Keywords

Anti-tumor; BI-2536; BRD4 inhibitors; c-Myc.

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