2. Academic Validation
  3. Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors

Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors

  • Eur J Med Chem. 2018 Jan 1:143:491-502. doi: 10.1016/j.ejmech.2017.11.073.
Haoliang Yuan 1,  Qiufeng Liu 2,  Li Zhang 3,  Shihe Hu 3,  Tiantian Chen 4,  Huifang Li 5,  Yadong Chen 3,  Yechun Xu 6,  Tao Lu 7
Affiliations

Affiliations

  • 1 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Institute of Pharmaceutical Research, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 2 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 4 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China.
  • 5 Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada.
  • 6 CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China. Electronic address: ycxu@simm.ac.cn.
  • 7 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Institute of Pharmaceutical Research, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: lutao@cpu.edu.cn.
PMID: 29202410 DOI: 10.1016/j.ejmech.2017.11.073
Abstract

The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors.

Keywords

Pharmacophore; Structural optimization; Virtual screening; X-ray crystallography; c-Met.

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