布鲁顿酪氨酸激酶
伊布替尼
化学
酪氨酸激酶
共价键
癌症研究
药理学
立体化学
生物化学
信号转导
白血病
免疫学
生物
慢性淋巴细胞白血病
有机化学
作者
Dou Dou,Wenjie Sha,Yanyan Diao,Rongrong Su,Yunjin Qiao,Zhixiao Yu,Zhenjiang Zhao,Honglin Li,Zhuo Chen,Yufang Xu
标识
DOI:10.1016/j.bioorg.2021.105541
摘要
Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI-1746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC50 values of 0.22 μM and 0.19 μM, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.
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