Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents

Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound 31e exhibited potent antiproliferative activity (IC50 (50% inhibitory concentration) = 0.026 μΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells. A mechanism study demonstrated that 31e induced G1 phase (First growth phase or G indicating gap) arrest, inhibited the phosphorylation of c-Met and its downstream signaling component, Akt (Protein Kinase B), and also inhibited the migration of hepatic carcinoma 97H cells.

• Publication year

  2019

• Venue

  Molecules

• Publication date

  2019-03-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.3390/molecules24061173PMID 30934578PMCID 6470795
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Recent advances in the discovery of small molecule c-Met Kinase inhibitors.

  2018cited by this paper
• An efficient synthesis of 2-thio-5-amino substituted benzoquinones via KI catalyzed cascade oxidation/Michael addition/oxidation starting from hydroquinone

  2016cited by this paper
• Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors.

  2015cited by this paper
• Potent antitumor activity of cabozantinib, a c‐MET and VEGFR2 inhibitor, in a colorectal cancer patient‐derived tumor explant model

  2015cited by this paper
• Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma

  2013cited by this paper
• Abstract LB-302: Potent antitumor activity of XL184 (cabozantinib), a c-MET and VEGFR2 inhibitor, in colorectal cancer patient-derived tumor explant models.

  2013cited by this paper
• Targeting MET in cancer: rationale and progress

  2012cited by this paper
• Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK).

  2011cited by this paper
• Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.

  2010cited by this paper
• ARQ 197, a Novel and Selective Inhibitor of the Human c-Met Receptor Tyrosine Kinase with Antitumor Activity

  2010cited by this paper
• Synthesis, structure-activity relationships, and biological profiles of a quinazolinone class of histamine H3 receptor inverse agonists.

  2008cited by this paper
• Drug development of MET inhibitors: targeting oncogene addiction and expedience

  2008cited by this paper
• An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.

  2007cited by this paper
• Synthesis and c-Src inhibitory activity of imidazo[1,5-a]pyrazine derivatives as an agent for treatment of acute ischemic stroke.

  2007cited by this paper
• Series Introduction: Invasive growth: from development to metastasis

  2002cited by this paper
• Oncogenic kinase signalling

  2001cited by this paper
• Clinical Significance of c-met Oncogene Alterations in Human Colorectal Cancer

  1999cited by this paper
• c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype.

  1998cited by this paper
• Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.

  1991cited by this paper
• THE WORLD HEALTH ORGANIZATION

  1954cited by this paper

• The importance of nitrile functionality: FDA-approved small molecules from 2021 to 2024

  2026cites this paper
• Imatinib-N-oxide through chemical modification of imatinib and investigation of in-vitro potential toxic metabolite formation

  2025cites this paper
• An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

  2024cites this paper
• New drug approvals for 2021: Synthesis and clinical applications.

  2022cites this paper
• Crystal structure of 4-(((2-(3-(1-(3-(3-cyanophenyl)-6-oxopyridazin-1(6H)-yl)ethyl)phenyl) pyrimidin-5-yl)oxy)methyl)-1-methylpiperidin-1-ium chloride monohydrate, C30H33N6O2Cl

  2022cites this paper
• Investigation of antitumor properties of semi-synthetic flavonoid derivatives on gynecological cancer cell lines

  2020cites this paper