Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma.

Abstract

The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM. Additionally, these pyrimidine derivatives also exhibited enhanced activity to block the proliferation of B-cell lymphoma cells compared with the representative BTK inhibitor ibrutinib. In particular, two structure-specific compounds 7b and 7e displayed stronger activity than reference agents in cell-based evaluation, with IC50 values lower than 10 μM. Further biological studies, including flow cytometric analysis, and a xenograft model for in vivo evaluation, also indicated their efficacy and low toxicity in the treatment of B-cell lymphoma. These findings provide a new insight for the development of novel anti-B-cell lymphoma drugs with multi-target actions.

• Authors: Yang Ge, Changyuan Wang, Shijie Song, Jiaxin Huang, Zhihao Liu, Yongming Li, Qiang Meng, Jianbin Zhang, Jihong Yao, Kexin Liu, Xiaodong Ma, Xiuli Sun
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 143 Pg. 1847-1857 (Jan 01 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29146136 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• BTK protein, human
• JAK3 protein, human
• Janus Kinase 3

Topics

• Adult
• Agammaglobulinaemia Tyrosine Kinase
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Humans
• Janus Kinase 3 (antagonists & inhibitors, metabolism)
• Leukocytes, Mononuclear (drug effects)
• Lymphoma, B-Cell (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, SCID
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship