School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China.
School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
Bioorg Med Chem. 2024 May 15;106:117752. doi: 10.1016/j.bmc.2024.117752. Epub 2024 May 9.
Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4-11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G/G phase, and inducing apoptosis in MV-4-11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.
溴结构域蛋白 4（BRD4）是 BET 家族的成员，其过表达与许多肿瘤的发生发展密切相关。BRD4 抑制在抗肿瘤方面具有巨大的治疗潜力，而泛 BRD4 抑制剂在临床试验中显示出剂量限制毒性和血小板减少的不良反应。为了提高临床效果，降低副作用，人们更加关注寻找 BD1 或 BD2 的选择性抑制剂。在此，通过对接指导的优化设计和合成了一系列吲哚-2-酮衍生物，以寻找 BRD4-BD1 选择性抑制剂，并评估了它们对 BRD4 的抑制作用和增殖活性。其中，化合物 21r 对 BRD4 具有很强的抑制活性（BD1 和 BD2 结构域的 IC值分别为 41 nM 和 313 nM），对增殖具有优异的抑制作用（对 HL-60、MV-4-11 和 HT-29 细胞的 IC 值分别为 4.64 ± 0.30 μM、0.78 ± 0.03 μM 和 5.57 ± 1.03 μM），并且对正常细胞 GES-1 细胞的毒性较低。进一步的研究表明，21r 通过降低原癌基因 c-Myc 的表达、阻断细胞周期在 G/G 期和诱导 MV-4-11 细胞凋亡，呈剂量依赖性方式抑制增殖。所有结果表明，化合物 21r 是一种有效的 BRD4 抑制剂，具有 BD1 选择性，在治疗白血病方面具有潜力。
