2. Academic Validation
  3. Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase

Pyridazinone derivatives displaying highly potent and selective inhibitory activities against c-Met tyrosine kinase

  • Eur J Med Chem. 2016 Jan 27:108:322-333. doi: 10.1016/j.ejmech.2015.11.042.
Yang Liu 1,  Shiyu Jin 1,  Xia Peng 2,  Dong Lu 1,  Limin Zeng 1,  Yiming Sun 2,  Jing Ai 3,  Meiyu Geng 4,  Youhong Hu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
  • 4 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China. Electronic address: yhhu@simm.ac.cn.
PMID: 26698536 DOI: 10.1016/j.ejmech.2015.11.042
Abstract

Over activation of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein we describe the design, synthesis and biological activities of novel, ATP-competitive, c-Met tyrosine kinase inhibitors that are members of the 6-aryl-2-(3-(heteroarylamino)benzyl)pyridazinone family. A structure-activity relationship (SAR) study of these substances led to identification of pyridazinone 19 as a highly selective and potent c-Met tyrosine inhibitor, which displays favorable pharmacokinetic properties in mice and significant antitumor activity against a c-Met driven EBC-1 tumor xenograft.

Keywords

Antitumor; Cyclization strategy; Pyridazinone; c-Met inhibitor.

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