2. Academic Validation
  3. A novel MMP-9 inhibitor exhibits selective inhibition in non-small-cell lung cancer harboring EGFR T790M mutation by blocking EGFR/STAT3 signaling pathway

A novel MMP-9 inhibitor exhibits selective inhibition in non-small-cell lung cancer harboring EGFR T790M mutation by blocking EGFR/STAT3 signaling pathway

  • Bioorg Chem. 2025 Mar 20:159:108393. doi: 10.1016/j.bioorg.2025.108393.
Liangping Li 1,  Minghan Lu 2,  Hui Wang 2,  Xuesong Ma 2,  Wenqing Du 2,  Yufei Zhao 2,  Shulan Zeng 3,  Yan Peng 4,  Guohai Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China; School of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, China.
  • 2 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 3 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: zengsl@gxnu.edu.cn.
  • 4 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: pengyan630@gxnu.edu.cn.
  • 5 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: zgh1207@gxnu.edu.cn.
PMID: 40121769 DOI: 10.1016/j.bioorg.2025.108393
Abstract

The T790M secondary mutation in EGFR confers therapeutic resistance to EGFR-TKIs, leading to poor outcomes. Non-small-cell lung Cancer (NSCLC) harboring EGFR T790M mutation is incurable and there is an urgent need for improved therapeutics. Here we report the identification of a small compound, MG-3C, that kills NSCLC cells with T790M mutation while sparing lung Cancer cells without T790M mutation. We found that MG-3C activity targets EGFR-STAT3 signaling pathway in NSCLC through direct inhibition of matrix metalloproteinase 9 (MMP-9), ultimately leading to G2/M phase arrest, growth inhibition and Apoptosis. Compared with the reported MMP-9 Inhibitor Ilomastat, MG-3C shows high Anticancer activity and affinity for targets. MG-3C forms hydrogen bonds with the ASP-113, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -9.04 kcal/mol, while Ilomastat forms hydrogen bonds with the GLN-169, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -5.98 kcal/mol. The spatial structure composed of ASP-113, ASP-201, and HIS-203 of MMP-9 provides a new coordinate for the design of MMP-9 inhibitors. Most importantly, subcutaneous and oral administration of MG-3C elicit dramatic regression of NSCLC xenograft tumors harboring T790M mutation as well as favorable biosafety profile in vivo, suggesting that MG-3C may be a potential candidate for NSCLC harboring T790M mutation.

Keywords

MMP-9 inhibitor; NSCLC; T790M mutation; Therapeutic resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15768
    98.39%, MMP Inhibitor
    MMP