title: SOMG-833, a novel selective c-MET inhibitor, blocks c-MET-dependent neoplastic effects and exerts antitumor activity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hao-tian
authors.initials: HT
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Chang-xi
authors.initials: CX
authors.lastname: He
authors.affiliation: 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.
authors.forename: Yin-chun
authors.initials: YC
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Jing-yu
authors.initials: JY
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: 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 yangjingyu2007@gmail.com mygeng@simm.ac.cn.
authors.forename: Mei-yu
authors.initials: MY
authors.lastname: Geng
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000590925:3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl)quinoline; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D016209:Interleukin-8; D010879:Piperazines; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met