2. Academic Validation
  3. Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR

Pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives as new multi-targeted inhibitors of Aurora A/B and KDR

  • Eur J Med Chem. 2018 Oct 5:158:428-441. doi: 10.1016/j.ejmech.2018.09.032.
Qiumeng Zhang 1,  Qianqian Shen 2,  Lixin Gao 3,  Linjiang Tong 2,  Jia Li 3,  Yi Chen 4,  Wei Lu 5
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China; National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3 National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: ychen@simm.ac.cn.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
PMID: 30241010 DOI: 10.1016/j.ejmech.2018.09.032
Abstract

Aurora A, Aurora B and Kinase Insert Domain-containing Receptor (VEGFR2/KDR/Flk-1) play essential roles in sustained Cancer growth. In the present study, eighteen pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine derivatives were designed and synthesized. Most of the prepared compounds exhibited obviously enzymatic (Aurora A/B and VEGFR2/KDR/Flk-1) activities. Among these analogs, compound 17g displayed significant Aurora A/B and VEGFR2/KDR/Flk-1 potencies with IC50 values of 46.2 nM, 37.6 nM and 21.6 nM, respectively. The results of further biological assays showed that compound 17g possessed moderate anti-proliferative activities against SNU-5, MKN-45 and MKN-74 cells lines, induced G2/M cell cycle arrest and Apoptosis in MKN-45, MKN-74, SGC-7901 and SNU-5 cell lines, provided acceptable pharmacokinetic profiles (F = 63.8%), and inhibited the proliferation of SNU-5 tumors in vivo of mice. All of the above results suggested that pyrazolo[4,3-b]pyrimido[4,5-e][1,4]diazepine could be developed as a promising scaffold of multiple Aurora A/B and VEGFR2/KDR/Flk-1 inhibitors and 17g was worth of further research as a multi-targeted lead compound.

Keywords

Anticancer; Aurora A; Aurora B; Heterocyclic; KDR; Multi-targeted.

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