A novel 2,5-diaminopyrimidine-based affinity probe for Bruton's tyrosine kinase.

Abstract

As a critical regulator of the B-cell receptor signaling pathway, Bruton's tyrosine kinase (Btk) has attracted intensive drug discovery efforts for treating B-cell lineage cancers and autoimmune disorders. In particular, covalent inhibitors targeting Cys481 in Btk have demonstrated impressive clinical benefits, and their companion affinity probes have been crucial in the drug development process. Recently, we have discovered a novel series of 2,5-diaminopyrimidine-based covalent irreversible inhibitors of Btk. Here, we present the discovery of a novel affinity Btk probe based on the aforementioned scaffold and demonstrate its usage in evaluating the target engagement of Btk inhibitors in live cells.

• Authors: Yingying Zuo, Yanxia Shi, Xitao Li, Yingqi Teng, Zhengying Pan
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 16136 (Nov 04 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26531233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Recombinant Proteins
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• pyrimidine

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Binding Sites
• Catalytic Domain
• Cell Line, Tumor
• Humans
• Inhibitory Concentration 50
• Kinetics
• Molecular Docking Simulation
• Protein Kinase Inhibitors (chemical synthesis, chemistry, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (chemical synthesis, chemistry, metabolism)
• Recombinant Proteins (biosynthesis, chemistry, isolation & purification)
• Structure-Activity Relationship