SOMG-833，一种新型选择性 c-MET 抑制剂，可阻断 c-MET 依赖性肿瘤效应并发挥抗肿瘤活性。
SOMG-833, a novel selective c-MET inhibitor, blocks c-MET-dependent neoplastic effects and exerts antitumor activity.
机构信息
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People's Republic of China (H.-t.Z., J.-y.Y.); Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (L.W., J.A., Y.C., C.-x.H., Y.-c.J., M.H., J.D., M.-y.G.) and CAS Key Laboratory of Receptor Research and Synthetic Organic & Medicinal Chemistry Laboratory (A.Z.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People's Republic of China (H.-t.Z., J.-y.Y.); Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (L.W., J.A., Y.C., C.-x.H., Y.-c.J., M.H., J.D., M.-y.G.) and CAS Key Laboratory of Receptor Research and Synthetic Organic & Medicinal Chemistry Laboratory (A.Z.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China
出版信息
J Pharmacol Exp Ther. 2014 Jul;350(1):36-45. doi: 10.1124/jpet.114.214817. Epub 2014 Apr 16.
The hepatocyte growth factor/c-MET signaling axis plays an important role in tumor cell proliferation, metastasis, and tumor angiogenesis, and therefore presents as an attractive target for cancer therapy. Notably, most small-molecule c-MET inhibitors currently undergoing clinical trials are multitarget inhibitors with the unwanted inhibition of additional kinases, often accounting for undesirable toxicity. Here, we discovered SOMG-833 [3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl) quinoline] as a potent and selective small-molecule c-MET inhibitor, with an average IC50 of 0.93 nM against c-MET, over 10,000-fold more potent compared with 19 tyrosine kinases, including c-MET family members and highly homologous kinases. SOMG-833 strongly suppressed c-MET-mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation, including MET gene amplification, MET gene fusion, and HGF-stimulated c-MET activation. In a panel of 24 human cancer or genetically engineered model cell lines, SOMG-833 potently inhibited c-MET-driven cell proliferation, whereas cancer cells lacking c-MET activation were markedly less sensitive (at least 15-fold) to the treatment. SOMG-833 also suppressed c-MET-mediated migration, invasion, urokinase activity, and invasive growth phenotype. In addition, inhibition of primary human umbilical vascular endothelial cell (HUVEC) proliferation and downregulation of plasma proangiogenic factor interleukin-8 secretion resulted from SOMG-833 treatment, suggesting its significant antiangiogenic properties. Together, these results led to the remarkable antitumor efficacy of SOMG-833 in vivo, as demonstrated in c-MET-dependent NIH-3T3/TPR-MET, U-87MG, and EBC-1 xenograft models. Collectively, our results suggested SOMG-833 as a promising candidate for highly selective c-MET inhibition and a powerful tool to investigate the sole role of MET kinase in cancer.
肝细胞生长因子/c-MET 信号轴在肿瘤细胞增殖、转移和肿瘤血管生成中发挥着重要作用，因此成为癌症治疗的一个有吸引力的靶点。值得注意的是，目前正在进行临床试验的大多数小分子 c-MET 抑制剂都是多靶点抑制剂，会意外抑制其他激酶，这往往导致不可取的毒性。在这里，我们发现 SOMG-833 [3-(4-甲基哌嗪-1-基)-5-(3-硝基苄基氨基)-7-(三氟甲基)喹啉]是一种有效的选择性小分子 c-MET 抑制剂，对 c-MET 的平均 IC50 为 0.93 nM，比包括 c-MET 家族成员和高度同源激酶在内的 19 种酪氨酸激酶的活性高 10000 多倍。SOMG-833 强烈抑制 c-MET 介导的信号转导，无论涉及 c-MET 激活的机制有多复杂，包括 MET 基因扩增、MET 基因融合和 HGF 刺激的 c-MET 激活。在 24 个人类癌症或基因工程模型细胞系的检测中，SOMG-833 能够有效抑制 c-MET 驱动的细胞增殖，而缺乏 c-MET 激活的癌细胞对该药物的敏感性明显降低（至少 15 倍）。SOMG-833 还抑制 c-MET 介导的迁移、侵袭、尿激酶活性和侵袭性生长表型。此外，SOMG-833 抑制原代人脐静脉内皮细胞（HUVEC）增殖和下调血浆促血管生成因子白细胞介素-8 的分泌，提示其具有显著的抗血管生成特性。总的来说，这些结果表明 SOMG-833 在体内具有显著的抗肿瘤疗效，在 c-MET 依赖性 NIH-3T3/TPR-MET、U-87MG 和 EBC-1 异种移植模型中得到了证实。综上所述，SOMG-833 有望成为一种高度选择性的 c-MET 抑制剂的候选药物，并为研究 MET 激酶在癌症中的单一作用提供有力工具。
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