2. Academic Validation
  3. Discovery of Dual Lysine Methyltransferase G9a and EZH2 Inhibitors with In Vivo Efficacy against Malignant Rhabdoid Tumor

Discovery of Dual Lysine Methyltransferase G9a and EZH2 Inhibitors with In Vivo Efficacy against Malignant Rhabdoid Tumor

  • J Med Chem. 2023 Apr 27;66(8):5685-5702. doi: 10.1021/acs.jmedchem.3c00003.
Yajie Shi 1,  Qiuyue Zhang 2,  Maoying Zhang 1,  Yongsong Chen 1,  Jianwen Sun 1,  Lu Chen 1,  Sen Liu 2,  Zhongbo Liu 3,  Jingyu Yang 2,  Chunfu Wu 2,  Zhonghui Zheng 4,  Lihui Wang 2,  Guoliang Chen 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 3 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
  • 4 Shandong Xinhua Pharmaceutical Co., Ltd., Zibo 255086, P. R. China.
PMID: 37021456 DOI: 10.1021/acs.jmedchem.3c00003
Abstract

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 15h displayed potent inhibitory activities against G9a (IC50 = 2.90 ± 0.05 nM) and EZH2 (IC50 = 4.35 ± 0.02 nM), superior antiproliferative profiles against RD (CC50 = 19.63 ± 0.18 μM) and SW982 (CC50 = 19.91 ± 0.50 μM) cell lines. In vivo, 15h 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 15h can inhibit tumor growth by specifically inhibiting EZH2 and G9a. Therefore, 15h is a potential Anticancer drug candidate for the treatment of malignant rhabdoid tumor.

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