Discovery of 7H-pyrrolo[2,3-d]pyrimidine derivatives as selective covalent irreversible inhibitors of interleukin-2-inducible T-cell kinase (Itk)

Guanghui Tang; Lihong Liu; Xueying Wang; Zhengying Pan

doi:10.1016/j.ejmech.2019.03.055

Discovery of 7H-pyrrolo[2,3-d]pyrimidine derivatives as selective covalent irreversible inhibitors of interleukin-2-inducible T-cell kinase (Itk)

Eur J Med Chem. 2019 Jul 1:173:167-183. doi: 10.1016/j.ejmech.2019.03.055. Epub 2019 Mar 26.

Authors

Guanghui Tang¹, Lihong Liu¹, Xueying Wang¹, 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: 30999237
DOI: 10.1016/j.ejmech.2019.03.055

Abstract

Interleukin-2-inducible T-cell kinase (Itk) plays an important role in multiple signal transduction pathways in T and mast cells, and is a potential drug target for treating inflammatory diseases, autoimmune diseases, and T cell leukemia/lymphoma. Herein, we describe the discovery of a series of covalent Itk inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold. Placing an appropriate substitution group at a hydration site of the ATP binding pocket of Itk and using a saturated heterocyclic ring as a linker to the reactive group were crucial for selectivity. The optimized compound 9 showed potent activity against Itk, excellent selectivity for Itk over Btk and other structurally related kinases, inhibition of phospholipase C-γ1 (PLC-γ1) phosphorylation in cells, and anti-proliferative effects against multiple T leukemia/lymphoma cell lines. Compound 9 can serve as a valuable compound for further determination of functions of Itk.

Keywords: 7H-pyrrolo[2,3-d]pyrimidine; Covalent inhibitor; Itk; Selectivity.

MeSH terms

Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Jurkat Cells
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidines
Recombinant Proteins
Protein-Tyrosine Kinases
emt protein-tyrosine kinase