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

Yu Teng; Xiang Lu; Maoxu Xiao; Zhenbang Li; Yumei Zou; Shengnan Ren; Yu Cheng; Guoshun Luo; Hua Xiang

doi:10.1016/j.ejmech.2020.112339

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. Epub 2020 May 4.

Authors

Yu Teng¹, Xiang Lu¹, Maoxu Xiao¹, Zhenbang Li¹, Yumei Zou¹, Shengnan Ren¹, Yu Cheng¹, Guoshun Luo², Hua Xiang³

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.

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
Agammaglobulinaemia Tyrosine Kinase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Triazines
Agammaglobulinaemia Tyrosine Kinase