School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2020 Dec 15;208:112780. doi: 10.1016/j.ejmech.2020.112780. Epub 2020 Aug 30.
Bromodomain protein 4 (BRD4) plays a crucial role in transcriptional regulation and is considered to be a viable drug target for cancer treatment. Herein, we designed and synthesized a series of indole-2-one derivatives through scaffold hopping drug design. Most of the compounds showed potent BRD4 inhibitory activities and anti-proliferation activities in cancer cell lines. Especially, compound 12j exhibited excellent BRD4 inhibitory activities (BD1 IC = 19 nM, BD2 IC = 28 nM) and anti-proliferation potency with IC values of 4.75 μM and 1.35 μM in HT-29 and HL-60 cells, respectively. Additionally, docking studies showed that the hydrophobic pocket next to KAc region and WPF shelf were critical to the activity of the compound. Compound 12j could arrest the cell-cycle progression of HT-29 cells into the G1 phase and reduce the expression of c-Myc. Moreover, compound 12j exhibited favorable oral pharmacokinetic properties. All the results demonstrated that compound 12j was a potent BRD4 inhibitor and had merely potential for colon cancer treatment.
溴结构域蛋白 4（BRD4）在转录调控中发挥着关键作用，被认为是癌症治疗的一个可行的药物靶点。在此，我们通过基于结构的药物设计，设计并合成了一系列吲哚-2-酮衍生物。大多数化合物在癌细胞系中表现出很强的 BRD4 抑制活性和抗增殖活性。特别是化合物 12j 表现出优异的 BRD4 抑制活性（BD1 IC=19 nM，BD2 IC=28 nM）和抗增殖活性，在 HT-29 和 HL-60 细胞中的 IC 值分别为 4.75 μM 和 1.35 μM。此外，对接研究表明，靠近 KAc 区域和 WPF 支架的疏水性口袋对化合物的活性至关重要。化合物 12j 可以将 HT-29 细胞的细胞周期阻滞在 G1 期，并降低 c-Myc 的表达。此外，化合物 12j 表现出良好的口服药代动力学性质。所有结果表明，化合物 12j 是一种有效的 BRD4 抑制剂，具有治疗结肠癌的潜力。
