Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma
| Autor: | Shijie Song, Yang Ge, Kexin Liu, Qiang Meng, Jianbin Zhang, Xiaodong Ma, Xiuli Sun, Changyuan Wang, Yongming Li, Jiaxin Huang, Zhihao Liu, Jihong Yao |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Lymphoma B-Cell Antineoplastic Agents Mice SCID Receptor tyrosine kinase Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine immune system diseases hemic and lymphatic diseases Drug Discovery Agammaglobulinaemia Tyrosine Kinase medicine Animals Humans Bruton's tyrosine kinase Structure–activity relationship B-cell lymphoma Protein Kinase Inhibitors Pharmacology Dose-Response Relationship Drug Molecular Structure biology Chemistry Janus kinase 3 Organic Chemistry Janus Kinase 3 Neoplasms Experimental General Medicine Protein-Tyrosine Kinases medicine.disease Lymphoma Mice Inbred C57BL 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Ibrutinib Leukocytes Mononuclear biology.protein Cancer research Phosphorylation Female Drug Screening Assays Antitumor |
| Zdroj: | European Journal of Medicinal Chemistry. 143:1847-1857 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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