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Issue 42, 2017
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Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

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Abstract

A series of 4,6-substituted thieno[3,2-d]pyrimidine derivatives as Bruton's tyrosine kinase (BTK) inhibitors are designed, synthesized and evaluated for their enzymatic inhibition and immunosuppressive activities. These derivatives exhibit varying inhibitory activities against BTK in vitro. Compound 8 is a novel potent BTK inhibitor which has an IC50 value of 29.9 nM, exerts excellent immunosuppressive activity by inhibiting the proliferation of B cells (IC50 = 284 nM), and shows low cytotoxicity (CC50 = 53 632 nM) on murine splenocytes. In addition, compound 8 displays considerable selectivity between T cells (IC50 > 10 μM) and B cells. Furthermore, enzymatic assays on more than twenty kinases confirm that compound 8 is more selective than the reference compound Olmutinib. In summary, the results suggest that compound 8 is a potential BTK inhibitor for further evaluation and modification of the C-4 and C-6 position of the thieno[3,2-d]pyrimidine scaffold, which could be considered a new strategy in the development of BTK inhibitors.

Graphical abstract: Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

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Supplementary files

Article information


Submitted
15 Apr 2017
Accepted
02 May 2017
First published
16 May 2017

This article is Open Access

RSC Adv., 2017,7, 26060-26069
Article type
Paper

Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

Q. Zhang, L. Zhang, J. Yu, H. Li, S. He, W. Tang, J. Zuo and W. Lu, RSC Adv., 2017, 7, 26060
DOI: 10.1039/C7RA04261B

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