Discovery and biological evaluation of N5-substituted 6,7-dioxo-6,7-dihydropteridine derivatives as potent Bruton's tyrosine kinase inhibitors

Medchemcomm. 2018 Mar 13;9(4):697-704. doi: 10.1039/c8md00019k.

Haiyang Chen ¹, Peiran Song ² ³ ⁴, Yanyan Diao ¹, Yongjia Hao ¹, Dou Dou ¹, Wanqi Wang ¹, Xiaoyu Fang ¹, Yanling Wang ¹, Zhenjiang Zhao ¹, Jian Ding ², Honglin Li ¹, Hua Xie ², Yufang Xu ¹

Affiliations

1 Shanghai Key Laboratory of New Drug Design , State Key Laboratory of Bioreactor Engineering , School of Pharmacy , East China University of Science & Technology , Shanghai 200237 , China . Email: hlli@ecust.edu.cn ; Email: yfxu@ecust.edu.cn ; ; Tel: +86 21 64250213.
2 Division of Anti-tumor Pharmacology , State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , Shanghai 201203 , China . Email: hxie@jding.dhs.org.
3 University of Chinese Academy of Sciences , Beijing 100049 , China.
4 School of Life Science and Technology , ShanghaiTech University , Shanghai 201210 , China.

PMID: 30108960 DOI: 10.1039/c8md00019k

Abstract

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 PLCγ2. 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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