2. Academic Validation
  3. Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma

Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma

  • J Med Chem. 2025 Feb 27;68(4):4196-4216. doi: 10.1021/acs.jmedchem.4c01947.
Nan Wang 1,  Xianxia Zeng 2,  Mengyang Xu 3,  Yamin Shi 4,  Jie Zhang 2,  Zhen Ling 2,  Xin Xie 2,  Tingsheng Qin 2,  Huaizheng Huang 2,  Jie Yang 2,  Ting Ma 1,  Linhong He 2
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 2 Pharmaceutical College, Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, Guangxi Medical University, Nanning, Guangxi 530021, China.
  • 3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China.
  • 4 Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
PMID: 39953991 DOI: 10.1021/acs.jmedchem.4c01947
Abstract

BMX, a member of the Tec family of kinases, plays a pivotal role in the occurrence and progression of cancers and multiple chronic inflammations. However, there are rarely BMX inhibitors reported, and the signaling pathways mediated by BMX are still poorly understood. In this study, a series of novel BMX inhibitors bearing the core of 1,3,5-triazin-2-amine were designed and synthesized by structural modifications from the lead compound B1c. Among them, compound B6a irreversibly and selectively inhibited BMX (IC50 = 12 nM) and displayed good antiproliferative activities in various Cancer cell lines. A mechanism study in gastric carcinoma HGC-27 and MGC-803 cells revealed that B6a promoted cell cycle arrest and Apoptosis, triggered protective Autophagy, and suppressed the BMX/Akt/mTOR pathway. Notably, although B6a's bioavailability was extremely low, it still exhibited excellent antitumor potency in the HGC-27 xenograft model with high safety, demonstrating that B6a was a promising BMX inhibitor and worth further exploration.

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