2. Academic Validation
  3. Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold

  • Bioorg Med Chem. 2015 Feb 1;23(3):564-78. doi: 10.1016/j.bmc.2014.12.002.
Xiaolong Jiang 1,  Hongyan Liu 2,  Zilan Song 3,  Xia Peng 2,  Yinchun Ji 2,  Qizheng Yao 4,  Meiyu Geng 2,  Jing Ai 5,  Ao Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: qz_yao@yahoo.com.cn.
  • 5 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
  • 6 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: aozhang@simm.ac.cn.
PMID: 25537530 DOI: 10.1016/j.bmc.2014.12.002
Abstract

A series of 3-amino-benzo[d]isoxazole-/3-aminoindazole-based compounds were designed, synthesized and pharmacologically evaluated as tyrosine kinase c-Met inhibitors. The SAR study was conducted leading to identification of nine compounds (8d, 8e, 12, 28a-d, 28h and 28i) with IC50s less than 10nM against c-Met. Compound 28a stood out as the most potent c-Met inhibitor displaying potent inhibitory effects both at enzymatic (IC50=1.8 nM) and cellular (IC50=0.18 μM on EBC-1 cells) levels. In addition, 28a had a relatively good selectivity compared to a panel of our in-house 14 RTKs.

Keywords

3-Amino-benzo[d]isoxazole; 3-Aminoindazole; Inhibitor; Non-small cell lung cancer; c-Met kinase.

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