2. Academic Validation
  3. The design and synthesis of selective and potent selenium-containing KRASG12D inhibitors

The design and synthesis of selective and potent selenium-containing KRASG12D inhibitors

  • Eur J Med Chem. 2025 Nov 15:298:118004. doi: 10.1016/j.ejmech.2025.118004.
Liping Zhou 1,  Yayuan Yang 1,  Bingzhong Chen 1,  Jie Wang 2,  Ping Zhang 1,  Yang Zhou 1,  Jinwei Zhang 2,  Xiaomei Ren 2,  Zhen Wang 2,  Weixue Huang 2,  Zhimin Zhang 1,  Xin Zhang 3,  Shingpan Chan 4,  Fengtao Zhou 5
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: zhangx617@jnu.edu.cn.
  • 4 Guangzhou Salustier BioSciences Co., Ltd, Kaiyuan Avenue, Guangzhou, 510530, China. Electronic address: chencb@lxpharma.cn.
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: fengtaozhou@jnu.edu.cn.
PMID: 40743812 DOI: 10.1016/j.ejmech.2025.118004
Abstract

KRASG12D is the most common KRAS mutation and a promising therapeutic target for various type cancers, particularly pancreatic Cancer. In this study, we employed a structure-based drug design approach to develop a series of 2-aminobenzo[b]selenophene-3-carbonitrile derivatives as potent and selective KRASG12D inhibitors. The representative compound (R)-5a effectively and selectively inhibited the proliferation of KRASG12D harboring AsPC-1 cells, with an IC50 value of 10 nM, while sparing Other KRASmut and KRASWT cell lines. Furthermore, compound (R)-5a suppressed KRAS downstream signaling, including ERK/MAPK pathway and induced Apoptosis and G0/G1 phase arrest in a dose-dependent manner. In addition, compound (R)-5a has good pharmacokinetic properties compared to MRTX1133. These findings demonstrate (R)-5a as a promising lead compound for the development of KRASG12D selective inhibitor.

Keywords

Cancer; Inhibitor; KRAS(G12D); Structure-based design; selenium.

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