Li Junhua, Hu Qingqing, Zhu Run, Dong Ruibo, Shen Hui, Hu Jiankang, Zhang Cheng, Zhang Xiaohan, Xu Tingting, Xiang Qiuping, Zhang Yan, Lin Bin, Zhao Linxiang, Wu Xishan, Xu Yong
China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2024 Dec 12;67(23):21577-21616. doi: 10.1021/acs.jmedchem.4c02516. Epub 2024 Nov 27.
Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor (XY153), we successfully identified (XY221) as the first BRD4 BD2-selective inhibitor. demonstrated potent binding affinity for BRD4 BD2 (IC = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. exhibited good liver microsomal stability ( > 120 min) and pharmacokinetic properties ( = 13.1%). These data indicate that may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research.
泛BD2抑制剂已被证明具有抗白血病作用，且与泛BET抑制剂相比，剂量限制性毒性更小。然而，有必要考虑抑制四种BET BD2蛋白所带来的潜在脱靶毒性。迄今为止，尚未有BRD4 BD2结构域选择性抑制剂的报道。基于我们之前的泛BD2抑制剂（XY153），我们成功鉴定出（XY221）作为首个BRD4 BD2选择性抑制剂。其对BRD4 BD2表现出强大的结合亲和力（IC = 5.8 nM），同时具有高泛BD2选择性（比BRD4 BD1高667倍）和BRD4 BD2结构域选择性（比BRD2/3/T BD2高9 - 32倍）。通过生物层干涉术（BLI）分析进一步证实了其对BRD4 BD2的选择性，显示出比其他BET BD2结构域高66 - 144倍的选择性。它表现出良好的肝微粒体稳定性（> 120分钟）和药代动力学性质（= 13.1%）。这些数据表明，XY221可能是推进BRD4 BD2表观遗传学研究的一个有价值的候选物。
