Liu Jing-Ying, Zhang Hong-En, Wang Cheng, Zhang Ping-Fan, Xu Yun-Gen, Shi Lei, Sun Li-Ping
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, PR China.
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, PR China.
Eur J Med Chem. 2025 Mar 5;285:117272. doi: 10.1016/j.ejmech.2025.117272. Epub 2025 Jan 13.
The bromodomain-containing protein 4 (BRD4) is an epigenetic regulatory 'reader' belonging to the bromodomain and extra-terminal domain (BET) family. Several studies have demonstrated that the high expression of BRD4 is closely related to the occurrence and development of various cancers, so BRD4 has become a promising target for cancer treatment. However, there are no drugs targeting BRD4 available on the market, the development of novel BRD4 inhibitors is of great significance. This paper describes a series of triazolopyridine derivatives exhibiting favorable BRD4 inhibitory activity, which have not been reported before. Among them, the representative compound 12m showed potent BRD4 BD1 inhibitory activity, of which the inhibition rate is better than the other compounds. In MV4-11 cell line, compound 12m also showed excellent anti-cancer activity (IC = 0.02 μM), which is superior to (+)-JQ1 (IC = 0.03 μM). Through molecular docking, it was discovered that compound 12m could combine with the acetyl-lysine binding site of BRD4 BD1 and form a hydrogen bond with a crucial amino acid residue Asn140. Additionally, compound 12m was found to have good metabolic stability with a clearance rate of only 0.3 μL/min/nm in mouse liver microsomes. Apoptosis experiments demonstrated that compound 12m induced apoptosis better than (+)-JQ1 at the same concentration, and the apoptosis rate of compound 12m increased from 43.2 % to 83.2 %. Subsequent in vivo pharmacokinetic testing of compound 12m in ICR mice yielded a good oral absorption and utilization of compound 12m (F = 44.8 %). The results indicate that triazolopyridine is an outstanding skeleton for developing novel BRD4 inhibitors, and compound 12m is a promising lead compound for further optimization and extensive clinical development.
含溴结构域蛋白4（BRD4）是一种属于溴结构域和额外末端结构域（BET）家族的表观遗传调控“读取器”。多项研究表明，BRD4的高表达与多种癌症的发生发展密切相关，因此BRD4已成为癌症治疗的一个有前景的靶点。然而，市场上尚无靶向BRD4的药物，开发新型BRD4抑制剂具有重要意义。本文描述了一系列具有良好BRD4抑制活性的三唑并吡啶衍生物，此前未见报道。其中，代表性化合物12m表现出较强的BRD4 BD1抑制活性，其抑制率优于其他化合物。在MV4-11细胞系中，化合物12m也表现出优异的抗癌活性（IC = 0.02 μM），优于（+）-JQ1（IC = 0.03 μM）。通过分子对接发现，化合物12m可与BRD4 BD1的乙酰赖氨酸结合位点结合，并与关键氨基酸残基Asn140形成氢键。此外，发现化合物12m具有良好的代谢稳定性，在小鼠肝微粒体中的清除率仅为0.3 μL/min/nm。凋亡实验表明，化合物12m在相同浓度下比（+）-JQ1诱导凋亡的效果更好，化合物12m的凋亡率从43.2%提高到83.2%。随后在ICR小鼠中对化合物12m进行的体内药代动力学测试表明，化合物12m具有良好的口服吸收和利用率（F = 44.8%）。结果表明，三唑并吡啶是开发新型BRD4抑制剂的优秀骨架，化合物12m是进一步优化和广泛临床开发的有前景的先导化合物。
