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
  • 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.