Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis

Weiqiang Xing; Jing Ai; Shiyu Jin; Zhangxing Shi; Xia Peng; Lang Wang; Yinchun Ji; Dong Lu; Yang Liu; Meiyu Geng; Youhong Hu

doi:10.1016/j.ejmech.2015.03.041

Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis

Eur J Med Chem. 2015 May 5:95:302-12. doi: 10.1016/j.ejmech.2015.03.041. Epub 2015 Mar 21.

Authors

Weiqiang Xing¹, Jing Ai², Shiyu Jin¹, Zhangxing Shi¹, Xia Peng², Lang Wang¹, Yinchun Ji², Dong Lu¹, Yang Liu¹, Meiyu Geng³, Youhong Hu⁴

Affiliations

¹ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China.
³ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
⁴ State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: yhhu@mail.shcnc.ac.cn.

PMID: 25827399
DOI: 10.1016/j.ejmech.2015.03.041

Abstract

A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline-pyridazinone 8a, containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition IC50 value of 17 nM.

Keywords: Anticancer; Docking study; Pyridazinone; c-Met inhibitor.

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Humans
Molecular Docking Simulation*
Protein Conformation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / chemistry
Proto-Oncogene Proteins c-met / metabolism*
Pyridazines / chemistry
Pyridazines / metabolism*
Pyridazines / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyridazines
pyridazine
Proto-Oncogene Proteins c-met