Sun Zhongya, Zhang Hao, Chen Zhifeng, Xie Yiqian, Jiang Hao, Chen Limin, Ding Hong, Zhang Yuanyuan, Jiang Hualiang, Zheng Mingyue, Luo Cheng
School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
Bioorg Med Chem Lett. 2017 May 1;27(9):2003-2009. doi: 10.1016/j.bmcl.2017.03.012. Epub 2017 Mar 9.
As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC value of 0.81±0.03μM. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72Å resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases.
作为一种表观遗传阅读器，BRD4调节对肿瘤细胞存活至关重要的重要下游基因的转录。靶向BRD4第一个溴结构域（BRD4-BD1）的小分子抑制剂在BRD4相关癌症的治疗中显示出有前景的潜力。通过基于AlphaScreen的高通量筛选试验，鉴定出一种新型小分子抑制剂，并将其命名为DCBD-005，它抑制BRD4-BD1与乙酰化赖氨酸之间的结合，IC值为0.81±0.03μM。化合物DCBD-005有效抑制人白血病MV4-11细胞的活力，导致细胞周期停滞，并诱导细胞凋亡。此外，化合物DCBD-005与BRD4-BD1的晶体结构在1.72Å分辨率下确定，揭示了先导化合物的结合机制，也为进一步基于结构的优化提供了坚实基础。这些结果表明，这种新型BRD4-BD1抑制剂DCBD-005有望开发成为治疗BRD4相关疾病的候选药物。
