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

Yang Liu; Shiyu Jin; Xia Peng; Dong Lu; Limin Zeng; Yiming Sun; Jing Ai; Meiyu Geng; Youhong Hu

doi:10.1016/j.ejmech.2015.11.042

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. Epub 2015 Nov 30.

Authors

Yang Liu¹, Shiyu Jin¹, Xia Peng², Dong Lu¹, Limin Zeng¹, Yiming Sun², Jing Ai³, Meiyu Geng⁴, Youhong Hu⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Humans
Mice
Models, Molecular
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridazines / chemical synthesis
Pyridazines / chemistry*
Pyridazines / pharmacology*
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridazines
Proto-Oncogene Proteins c-met