Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors,Journal of Medicinal Chemistry

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Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-15 , DOI: 10.1021/acs.jmedchem.4c00640
Chunju Yang ₁ , Bang Li ₁ , Zongbo Feng ₁ , Huaxuan Li ₁ , Hong Yang ₂ , Zhenjiao Yang ₁ , Li Liu ₁ , Qiongyu Shi ₂ , Hong Wang _{1,

3} , Zhong-Zhu Chen ₄ , Xun Huang _{2,

5} , Junjian Wang _{1,

3} , Yuanxiang Wang _{1,

3}

Affiliation

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 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. 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 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

中文翻译：

发现一种治疗实体瘤的高效赖氨酸甲基转移酶 G9a/NSD2 双重抑制剂

G9a 和 NSD2 都被认为是有前途的癌症治疗靶点。然而，G9a 抑制剂仅对实体瘤显示出中等抑制活性，而 NSD2 抑制剂仅限于治疗血液系统恶性肿瘤。受双靶点抑制剂在提高效率方面显示出巨大潜力的优势的启发，我们开发了一系列高效的 G9a/NSD2 双重抑制剂来治疗实体瘤。与选择性 G9a 抑制剂 3 和 NSD2 抑制剂 15 相比，候选药物 16 的抗增殖活性显著增强。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卓越的效力。此外，它有效抑制了细胞中 G9a 和 NSD2 的催化功能，并在 PANC-1 异种移植模型中表现出显着的抗肿瘤功效，具有良好的安全性。因此，化合物 16 作为一种高效的 G9a/NSD2 双重抑制剂，为治疗实体瘤提供了一种有吸引力的抗癌候选药物。

更新日期：2024-07-15

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