Li Liangping, Lu Minghan, Wang Hui, Ma Xuesong, Du Wenqing, Zhao Yufei, Zeng Shulan, Peng Yan, Zhang Guohai
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.
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.
Bioorg Chem. 2025 Jun 1;159:108393. doi: 10.1016/j.bioorg.2025.108393. Epub 2025 Mar 20.
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.
表皮生长因子受体（EGFR）中的T790M二次突变赋予了对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的治疗抗性，导致预后不良。携带EGFR T790M突变的非小细胞肺癌（NSCLC）无法治愈，因此迫切需要改进治疗方法。在此，我们报告了一种小分子化合物MG-3C的鉴定，该化合物可杀死携带T790M突变的NSCLC细胞，同时不损伤无T790M突变的肺癌细胞。我们发现MG-3C的活性通过直接抑制基质金属蛋白酶9（MMP-9）靶向NSCLC中的EGFR-STAT3信号通路，最终导致G2/M期阻滞、生长抑制和细胞凋亡。与已报道的MMP-9抑制剂伊洛马司他相比，MG-3C显示出高抗癌活性和对靶点的亲和力。MG-3C与MMP-9的ASP-113、ASP-201和HIS-203氨基酸残基形成氢键，对接分数为-9.04千卡/摩尔，而伊洛马司他与MMP-9的GLN-169、ASP-201和HIS-203氨基酸残基形成氢键，对接分数为-5.98千卡/摩尔。由MMP-9的ASP-113、ASP-201和HIS-203组成的空间结构为MMP-9抑制剂的设计提供了新的坐标。最重要的是，皮下和口服MG-3C可使携带T790M突变的NSCLC异种移植瘤显著消退，且在体内具有良好的生物安全性，这表明MG-3C可能是携带T790M突变的NSCLC的潜在候选药物。
