Discovery of selective irreversible inhibitors of B-Lymphoid tyrosine kinase (BLK)

Tiancheng Fu; Yingying Zuo; Zhenpeng Zhong; Xuan Chen; Zhengying Pan

doi:10.1016/j.ejmech.2021.114051

Discovery of selective irreversible inhibitors of B-Lymphoid tyrosine kinase (BLK)

Eur J Med Chem. 2022 Feb 5:229:114051. doi: 10.1016/j.ejmech.2021.114051. Epub 2021 Dec 16.

Authors

Tiancheng Fu¹, Yingying Zuo¹, Zhenpeng Zhong¹, Xuan Chen¹, Zhengying Pan²

Affiliations

¹ State Key Laboratory of Chemical Oncogenomics, Engineering Laboratory for Chiral Drug Synthesis, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China.
² State Key Laboratory of Chemical Oncogenomics, Engineering Laboratory for Chiral Drug Synthesis, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, China. Electronic address: panzy@pkusz.edu.cn.

PMID: 34952433
DOI: 10.1016/j.ejmech.2021.114051

Abstract

B-lymphoid tyrosine kinase (BLK), a member of the SRC family nonreceptor tyrosine kinase, is involved in the B-cell receptor (BCR) signaling pathway and B cell development and function. Dysregulation of BLK is associated with autoimmune diseases and cancer. However, there is an absence of good tool compounds for BLK, and the molecular mechanisms by which BLK mediates physiological and pathological processes are poorly understood. Herein, we present the discovery of a novel series of selective and irreversible inhibitors of BLK with nanomolar potency against BLK in biochemical and cellular assays. Compound 25 demonstrated potent antiproliferative activities against several B cell lymphoma cell lines. These compounds constitute the first series of selective inhibitors developed for BLK and could help expedite the exploration of BLK functions.

Keywords: B cell lymphoma; BLK; Covalent inhibitor; Tyrosine kinase.

MeSH terms

Adenosine Triphosphate / chemistry
Adenosine Triphosphate / metabolism
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Humans
Molecular Docking Simulation
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / metabolism

Substances

Protein Kinase Inhibitors
Adenosine Triphosphate
BLK protein, human
src-Family Kinases