Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Lingang Laboratory, Shanghai 200031, P. R. China.
J Med Chem. 2024 Sep 26;67(18):16072-16087. doi: 10.1021/acs.jmedchem.4c00640. Epub 2024 Jul 15.
Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor and NSD2 inhibitor . In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.
G9a 和 NSD2 均被认为是癌症治疗有前途的治疗靶点。然而，G9a 抑制剂仅对实体瘤表现出中等抑制活性，而 NSD2 抑制剂仅限于治疗血液系统恶性肿瘤。受双靶抑制剂在提高效率方面具有巨大潜力的启发，我们开发了一系列高效的 G9a/NSD2 双抑制剂来治疗实体瘤。候选物与选择性 G9a 抑制剂和 NSD2 抑制剂相比，表现出更强的抗增殖活性。此外，它在抑制集落形成、诱导细胞凋亡和阻断癌细胞转移方面表现出优异的活性。此外，它还能有效地抑制细胞中 G9a 和 NSD2 的催化功能，并在具有良好安全性的 PANC-1 异种移植模型中显示出显著的抗肿瘤疗效。因此，作为一种高效的 G9a/NSD2 双抑制剂，化合物是一种有吸引力的抗癌药物候选物，可用于治疗实体瘤。
