Discovery and Biological evaluation of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as potent Bruton's tyrosine kinase inhibitors

Bioorg Med Chem. 2019 Aug 1;27(15):3390-3395. doi: 10.1016/j.bmc.2019.06.023.

Yanyan Diao ¹, Xiaoyu Fang ¹, Peiran Song ², Mengzhen Lai ³, Linjiang Tong ⁴, Yongjia Hao ¹, Dou Dou ¹, Yingqiang Liu ⁴, Jian Ding ², Zhenjiang Zhao ⁵, Hua Xie ⁶, Honglin Li ⁷

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.
2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China; School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China.
4 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
5 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. Electronic address: zhjzhao@ecust.edu.cn.
6 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: hxie@simm.ac.cn.
7 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. Electronic address: hlli@ecust.edu.cn.

PMID: 31221612 DOI: 10.1016/j.bmc.2019.06.023

Abstract

Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton's tyrosine kinase (Btk), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent Btk inhibitors. Compounds 17 and 18 displayed strong Btk inhibitory activities in the enzymatic inhibition assay, with the IC₅₀ values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC₅₀ = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against Btk and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 µM.

Keywords

B-cell malignancies; Bruton’s tyrosine kinase; Cellular activities; Potent inhibitors; Structure-activity relationship.

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