发现具有体内抗横纹肌肉瘤疗效的双赖氨酸甲基转移酶 G9a 和 EZH2 抑制剂。
Discovery of Dual Lysine Methyltransferase G9a and EZH2 Inhibitors with In Vivo Efficacy against Malignant Rhabdoid Tumor.
机构信息
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
出版信息
J Med Chem. 2023 Apr 27;66(8):5685-5702. doi: 10.1021/acs.jmedchem.3c00003. Epub 2023 Apr 6.
In recent years, it has been proposed that G9a/EZH2 dual inhibition is a promising cancer treatment strategy. Herein, we present the discovery of G9a/EZH2 dual inhibitors that merge the pharmacophores of G9a and EZH2 inhibitors. Among them, the most promising compound displayed potent inhibitory activities against G9a (IC = 2.90 ± 0.05 nM) and EZH2 (IC = 4.35 ± 0.02 nM), superior antiproliferative profiles against RD (CC = 19.63 ± 0.18 μM) and SW982 (CC = 19.91 ± 0.50 μM) cell lines. , achieved significant antitumor efficacy in a xenograft mouse model of human rhabdoid tumor with a tumor growth inhibitory rate of 86.6% without causing observable toxic effects. The on-target activity assays illustrated that compound can inhibit tumor growth by specifically inhibiting EZH2 and G9a. Therefore, is a potential anticancer drug candidate for the treatment of malignant rhabdoid tumor.
近年来，有人提出 G9a/EZH2 双重抑制可能是一种有前途的癌症治疗策略。在此，我们介绍了融合 G9a 和 EZH2 抑制剂药效团的 G9a/EZH2 双重抑制剂的发现。其中，最有前途的化合物 显示出对 G9a（IC = 2.90 ± 0.05 nM）和 EZH2（IC = 4.35 ± 0.02 nM）的强大抑制活性，对 RD（CC = 19.63 ± 0.18 μM）和 SW982（CC = 19.91 ± 0.50 μM）细胞系具有优异的抗增殖作用。 在人横纹肌肉瘤异种移植小鼠模型中， 表现出显著的抗肿瘤疗效，肿瘤生长抑制率为 86.6%，且没有观察到明显的毒性作用。靶标活性测定表明，化合物 可以通过特异性抑制 EZH2 和 G9a 来抑制肿瘤生长。因此， 是治疗恶性横纹肌肉瘤的一种有潜力的抗癌药物候选物。
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