Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2024 Jan 25;67(2):1513-1532. doi: 10.1021/acs.jmedchem.3c02104. Epub 2024 Jan 4.
Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of -BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound (IC = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to (IC = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (: 2583-fold; : 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis . Excellent antitumor efficacy with was achieved in an MV;411 mouse xenograft model. Pleasingly, compound (hERG IC > 30 μM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with (hERG IC = 2.8 μM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.
Bromodomain-selective BET 抑制已成为改善 BET 抑制剂安全性的一种很有前途的策略。在此，我们报告了发现强效的苯氧基芳基吡啶酮作为高度 BD2 选择性 BET 抑制剂。化合物 （IC = 2.9 nM）与 （IC = 1.0 nM）相比，对 BRD4 BD2 的抑制活性相当，对 BRD4 BD1 的选择性显著提高（：2583 倍；：344 倍）。该先导化合物通过诱导 G0/G1 期阻滞和细胞凋亡，显著抑制急性髓系白血病（AML）细胞系的增殖。在 MV;411 小鼠异种移植模型中，化合物 表现出优异的抗肿瘤疗效。令人高兴的是，与 （hERG IC = 2.8 μM）相比，化合物 （hERG IC > 30 μM）对人 Ether-à-go-go 相关基因（hERG）离子通道的抑制作用较弱。这项工作为开发更有效和安全的 BET 抑制剂作为抗癌药物提供了一个有前途的 BD2 选择性先导化合物。
