2. Academic Validation
  3. Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship

Difuran-substituted quinoxalines as a novel class of PI3Kα H1047R mutant inhibitors: Synthesis, biological evaluation and structure-activity relationship

  • Eur J Med Chem. 2018 Sep 5:157:37-49. doi: 10.1016/j.ejmech.2018.07.061.
Ning Zhang 1,  Zhimei Yu 1,  Xiaohong Yang 1,  Yan Zhou 2,  Qing Tang 1,  Ping Hu 1,  Jia Wang 2,  Shao-Lin Zhang 3,  Ming-Wei Wang 4,  Yun He 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China.
  • 2 The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, PR China.
  • 3 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: zhangsl@cqu.edu.cn.
  • 4 The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 189 Guo Shou Jing Road, Shanghai, 201203, PR China. Electronic address: mwwang@simm.ac.cn.
  • 5 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing, 401331, PR China. Electronic address: yun.he@cqu.edu.cn.
PMID: 30071408 DOI: 10.1016/j.ejmech.2018.07.061
Abstract

Phosphatidylinositol 3-kinase α (PI3Kα) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for Cancer treatment. We identified a structurally novel PI3Kα H1047R mutant inhibitor Hit-01 (EC50 = 76.0 μM) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3Kα H1047R mutant with an EC50 value of 0.137 μM, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3Kα H1047R function. Cell viability assay revealed that 7b inhibited HCT116 Cancer cell growth with an IC50 value of 11.23 μM. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell Apoptosis via up-regulation of Caspase-3, Caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3Kα inhibitors.

Keywords

Anticancer drug; Apoptosis; Phosphatidylinositol 3-kinase inhibitor; Proliferation; Structure-activity relationship.

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