Discovery of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors

• Published in: Chinese chemical letters Vol. 31; no. 2; pp. 418 - 422
• Main Authors: Wang, Shuai, Shen, Dandan, Zhao, Lijie, Yuan, Xiaohan, Cheng, Jialing, Yu, Bin, Zheng, Yichao, Liu, Hongmin
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.02.2020; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China&School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China%Key Laboratory of Technology of Drug Preparation, Ministry of Education of China & School of Pharmaceutical Sciences, Zhengzhou University,Zhengzhou 450001, China
• Subjects: [1,2,4]triazolo[1,5-a]pyrimidine; AML treatment; BRD4 inhibitor; Epigenetic regulation; THP-1 cells; THP-1 cells; AML treatment; Epigenetic regulation; [1,2,4]triazolo[1,5-a]pyrimidine; BRD4 inhibitor; 5-a]pyrimidine; 1; 2; 4]triazolo
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2019.08.029

[Display omitted] New [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibit BRD4 and show potential for AML treatment. [Display omitted] Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC50 values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC50 value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and up-regulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.