2. Academic Validation
  3. Discovery of potent and highly selective covalent inhibitors of Bruton's tyrosine kinase bearing triazine scaffold

Discovery of potent and highly selective covalent inhibitors of Bruton's tyrosine kinase bearing triazine scaffold

  • Eur J Med Chem. 2020 Aug 1:199:112339. doi: 10.1016/j.ejmech.2020.112339.
Yu Teng 1,  Xiang Lu 1,  Maoxu Xiao 1,  Zhenbang Li 1,  Yumei Zou 1,  Shengnan Ren 1,  Yu Cheng 1,  Guoshun Luo 2,  Hua Xiang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: gsluo@cpu.edu.cn.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xianghua@cpu.edu.cn.
PMID: 32402933 DOI: 10.1016/j.ejmech.2020.112339
Abstract

Bruton's tyrosine kinase (Btk), as a key regulator of the B cell receptor (BCR) signaling pathway, is an attractive therapeutic target for the treatment of various diseases such as leukemia and B-cell malignancies. Herein, a series of compounds bearing 1, 3, 5-triazine core were prepared, and their biological activities on Btk were determined. Then the molecular docking study and ADME property prediction were made and a highly potent selective Btk Inhibitor B8 (IC50 = 21.0 nM) was discovered. Compound B8 exhibited excellent activity with 5.14 nM inhibition of Raji cells and 6.14 nM inhibition of Ramos cells respectively. Additionally, B8 potently inhibited Btk kinase Y223 auto-phosphorylation, arrested cell cycle in G2/M phase and induced Apoptosis in Ramos cells. The high selectivity for Btk and high potency in TMD8 cells of B8 suggested a low risk of off-target related adverse effects. Further molecular docking and dynamic simulation on B8 furnished insights into its binding profile within Btk. With significant efficacy in cellular assays and good ADME and safety profiles, B8 can be identified as a promising Btk Inhibitor worthy of further profiling.

Keywords

1; 3; 5-Triazine; B-Cell malignancies; BTK; Leukemia.

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