2. Academic Validation
  3. Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines

Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines

  • Eur J Med Chem. 2019 Sep 15;178:767-781. doi: 10.1016/j.ejmech.2019.06.035.
Xiaofeng Guo 1,  Dongyan Yang 2,  Zhijin Fan 3,  Nailou Zhang 1,  Bin Zhao 1,  Chun Huang 4,  Fangjie Wang 4,  Rongji Ma 4,  Meng Meng 5,  Youcai Deng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, PR China.
  • 2 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, PR China. Electronic address: yangdy@nankai.edu.cn.
  • 3 State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, PR China. Electronic address: fanzj@nankai.edu.cn.
  • 4 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
  • 5 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, 400038, China. Electronic address: keven190@sina.com.
  • 6 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), Chongqing, 400038, China. Electronic address: youcai.deng@tmmu.edu.cn.
PMID: 31234030 DOI: 10.1016/j.ejmech.2019.06.035
Abstract

By the analysis of different binding modes with Bruton's tyrosine kinase (Btk), series of novel diphenylthiazole derivatives were rationally designed, synthesized and characterized. Biologically evaluation in biochemistry and cellular assay indicated that, compounds 5m, 5o, 6b, 6c, 6g, 6i, 7h, 7i, 7k, 7m, 7n, 7o and 7s exhibited improved potency against Ramos cell (IC50 = 1.36-8.60 μM) and Raji cell (IC50 = 1.20-14.04 μM) as compared with ibrutinib (IC50 = 14.69 and 15.99 μM, respectively). Especially, compounds 7m and 7n showed 10-time improved potency against Ramos cell viability over ibrutinib. Compound 6b improved 13-fold activity against Raji cell viability than ibrutinib. In addition, active compound 7o potently inhibited C481S mutant Btk with IC50 value of 0.061 μM. Apoptosis analysis of both Ramos and Raji cells indicated that 7o was remarkably more potent than CGI-1746 and ibrutinib. Compound 7o potently inhibited Btk Y223 phosphorylation in Raji cells, and arrested cell cycle progression in the G0/G1 phase in Raji and Ramos cells. This study expanded the structural diversity of Btk inhibitors and compound 7o was discovered as an active lead inhibitor with great potential for further studies.

Keywords

Activity; B cell lymphoma; BTK inhibitor; Diphenylthiazole; Docking mode.

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