Qian Ding, Jianghong Cai, Li Jin, Wei Hu, Wu Song, Peter Rose, Zhiyuan Tang, Yangyang Zhan, Leilei Bao, Wei Lei, Yi Zhun Zhu
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引用次数: 0
摘要
SMYD3(含 SET 和 MYND 结构域的 3)是一种组蛋白赖氨酸甲基转移酶,在不同类型的癌症中高度表达,是开发新型抗肿瘤疗法的一个有前景的表观遗传学靶点。目前尚未开发出治疗癌症的该蛋白选择性抑制剂。因此,本研究介绍了根据 SMYD3 结构筛选和合成的新型小分子 ZYZ384 的开发和表征情况。虚拟筛选最初用于确定先导化合物,随后通过修饰得到新型分子。研究人员利用多种技术对这些新型分子与 SMYD3 蛋白的结合亲和力和抑制活性进行了化合物筛选;并利用多种癌症细胞系对其抗肿瘤活性进行了体外评估。此外,还建立了肿瘤裸鼠模型,并在体内测定了所选分子的活性。为探索抗肿瘤机制,还进行了 RNA-seq 和芯片-seq 研究。这项研究发现了一种靶向SMYD3的新型小分子ZYZ384,它具有抗肿瘤活性,通过减少Rac1启动子的H3K4三甲基化,通过AKT通路引发肿瘤细胞周期停滞,从而抑制肝细胞癌肿瘤的生长。
A novel small molecule ZYZ384 targeting SMYD3 for hepatocellular carcinoma via reducing H3K4 trimethylation of the Rac1 promoter
SMYD3 (SET and MYND domain-containing 3) is a histone lysine methyltransferase highly expressed in different types of cancer(s) and is a promising epigenetic target for developing novel antitumor therapeutics. No selective inhibitors for this protein have been developed for cancer treatment. Therefore, the current study describes developing and characterizing a novel small molecule ZYZ384 screened and synthesized based on SMYD3 structure. Virtual screening was initially used to identify a lead compound and followed up by modification to get the novel molecules. Several technologies were used to facilitate compound screening about these novel molecules' binding affinities and inhibition activities with SMYD3 protein; the antitumor activity has been assessed in vitro using various cancer cell lines. In addition, a tumor-bearing nude mice model was established, and the activity of the selected molecule was determined in vivo. Both RNA-seq and chip-seq were performed to explore the antitumor mechanism. This work identified a novel small molecule ZYZ384 targeting SMYD3 with antitumor activity and impaired hepatocellular carcinoma tumor growth by reducing H3K4 trimethylation of the Rac1 promoter triggering the tumor cell cycle arrest through the AKT pathway.