2. Academic Validation
  3. Design, synthesis and biological evaluation of pyrazol-furan carboxamide analogues as novel Akt kinase inhibitors

Design, synthesis and biological evaluation of pyrazol-furan carboxamide analogues as novel Akt kinase inhibitors

  • Eur J Med Chem. 2016 Jul 19:117:47-58. doi: 10.1016/j.ejmech.2016.03.074.
Wenhu Zhan 1,  Lei Xu 2,  Xiaowu Dong 1,  Jun Dong 1,  Xiao Yi 1,  Xiaodong Ma 1,  Ni Qiu 1,  Jia Li 2,  Bo Yang 1,  Yubo Zhou 3,  Yongzhou Hu 4
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
  • 4 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address: huyz@zju.edu.cn.
PMID: 27089211 DOI: 10.1016/j.ejmech.2016.03.074
Abstract

A series of novel pyrazol-furan carboxamide analogues were designed, synthesized and biologically evaluated for their Akt1 inhibitory activities, as well as anti-proliferative efficacies against HCT116 and OVCAR-8 cell lines. Most compounds exhibited moderate to excellent Akt1 inhibitory activities, together with favorable cytotoxicities. Further kinase selectivity assay of the most promising compound 25e illustrated that it was also potent against the structurally related AGC kinases, including Akt2, Akt3, ROCK1 and PKA, but was specific over kinases from Other subfamilies. In addition, the Western blot analysis indicated that 25e could significantly suppress the phosphorylation level of Akt substrate GSK3β in PC-3 cell. Moreover, 25e demonstrated a concentration-dependent inhibition of phosphorylation of PRAS40 in LNCaP cell, with IC50 value of 30.4 nM.

Keywords

Akt1 inhibitor; Cancer; Cytotoxicity; Molecular docking; Synthesis.

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