Synthesis and structure-activity relationship study of pyrazolo[3,4-d]pyrimidines as tyrosine kinase RET inhibitors

  • Bioorg Med Chem Lett. 2017 Jun 1;27(11):2544-2548. doi: 10.1016/j.bmcl.2017.03.088.
Chengyan Wang  1 ,  Hongchun Liu  2 ,  Zilan Song  3 ,  Yinchun Ji  2 ,  Li Xing  3 ,  Xia Peng  2 ,  Xisheng Wang  4 ,  Jing Ai  5 ,  Meiyu Geng  2 ,  Ao Zhang  6
Affiliations
  • 1. Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, 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. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China. Electronic address: [email protected].
  • 5. 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: [email protected].
  • 6. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
PMID: 28404375 DOI: 10.1016/j.bmcl.2017.03.088
Abstract

Three series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized and evaluated as RET kinase inhibitors. Compounds 23a and 23c were identified to show significant activity both in the biochemical and the BaF3/CCDC6-RET cell assays. Compound 23c was found to significantly inhibit RET phosphorylation and down-stream signaling in BaF3/CCDC6-RET cells, confirming its potent cellular RET-targeting profile. Different from Other RET inhibitors with equal potency against KDR that associated with severe toxicity, 23c did not show significant KDR-inhibition even at the concentration of 1μM. These results demonstrated that 23c is a potent and selective RET Inhibitor.

Keywords
Anticancer; Cell proliferation; Pyrazolo[3,4-d]pyrimidine; Structure-activity relationship; Tyrosine kinase RET.