Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
College of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, PR China; Center for Drug Evaluation, NMPA, 128 Jianguo Road, Beijing 100022, PR China.
Bioorg Chem. 2021 Jun;111:104849. doi: 10.1016/j.bioorg.2021.104849. Epub 2021 Mar 22.
Accumulating researches have contributed much effect to discover novel chemotherapeutic drug for leukemia with expeditious curative effect, of which bromodomain-containing protein 4 (BRD4) inhibitor is considered as a eutherapeutic drug which has presented efficient cell proliferation suppression effect. In this study, we disclosed a series of phenylisoxazole sulfonamide derivatives as potent BRD4 inhibitors. Especially, compound 58 exhibited robust inhibitory potency toward BRD4-BD1 and BRD4-BD2 with IC values of 70 and 140 nM, respectively. In addition, compound 58 significantly suppressed cell proliferation of leukemia cell lines HL-60 and MV4-11 with IC values of 1.21 and 0.15 μM. In-depth study of the biological mechanism of compound 58 exerted its tumor suppression effect via down-regulating the level of oncogene c-myc. Moreover, in vivo pharmacokinetics (PK) study was conducted and the results demonstrated better pharmacokinetics features versus (+)-JQ1. In summary, our study discovers that compound 58 represents as a novel BRD4 inhibitor for further investigation in development of leukemia inhibitor with potentiality.
积累的研究为发现具有快速疗效的新型白血病化疗药物做出了重要贡献，其中溴结构域蛋白 4（BRD4）抑制剂被认为是一种有效的治疗药物，具有有效的细胞增殖抑制作用。在这项研究中，我们揭示了一系列苯并异恶唑磺酰胺衍生物作为有效的 BRD4 抑制剂。特别是化合物 58 对 BRD4-BD1 和 BRD4-BD2 表现出很强的抑制活性，IC 值分别为 70 和 140 nM。此外，化合物 58 显著抑制白血病细胞系 HL-60 和 MV4-11 的细胞增殖，IC 值分别为 1.21 和 0.15 μM。通过下调癌基因 c-myc 的水平，深入研究了化合物 58 发挥其肿瘤抑制作用的生物学机制。此外，还进行了体内药代动力学（PK）研究，结果表明与（+）-JQ1 相比，化合物 58 具有更好的 PK 特征。综上所述，我们的研究发现，化合物 58 作为一种新型的 BRD4 抑制剂，具有进一步开发白血病抑制剂的潜力。
