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

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

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: xshengwang77@mail.ustc.edu.cn.
  • 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: jai@simm.ac.cn.
  • 6 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: aozhang@simm.ac.cn.
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 VEGFR2/KDR/Flk-1 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.

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