Journal
MEDCHEMCOMM
Volume 9, Issue 4, Pages 697-704Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8md00019k
Keywords
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Funding
- National Key Research and Development Program [2016YFA0502304]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) [U1501501]
- Fundamental Research Funds for the Central Universities
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Bruton's tyrosine kinase (BTK) plays a critical role in B cell receptor (BCR)-mediated signaling pathways responsible for the development and function of B cells, which makes it an attractive target for the treatment of many types of B-cell malignancies. Herein, a series of N5-substituted 6,7-dioxo-6,7-dihydropteridine-based, irreversible BTK inhibitors were reported with IC50 values ranging from 1.9 to 236.6 nM in the enzymatic inhibition assay. Compounds 6 and 7 significantly inhibited the proliferation of Ramos cells which overexpress the BTK enzyme, as well as the autophosphorylation of BTK at Tyr223 and the activation of its downstream signaling molecule PLC gamma 2. Overall, this series of compounds could provide a promising starting point for further development of potent BTK inhibitors for B-cell malignancy treatment.
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