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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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Publication details

The article was received on 15 Apr 2017, accepted on 02 May 2017 and first published on 16 May 2017


Article type: Paper
DOI: 10.1039/C7RA04261B
RSC Adv., 2017,7, 26060-26069
  • Open access: Creative Commons BY license
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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

    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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