2. Academic Validation
  3. Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives

  • Bioorg Med Chem. 2019 Mar 15;27(6):944-954. doi: 10.1016/j.bmc.2019.01.028.
Zutao Yu 1,  Zhuo Chen 1,  Qiongli Su 2,  Shiqi Ye 3,  Hongbo Yuan 4,  Mengni Kuai 5,  Meng Lv 1,  Zhijun Tu 1,  Xiaoping Yang 2,  RangRu Liu 6,  Gaoyun Hu 1,  Qianbin Li 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China.
  • 2 Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410013, Hunan, PR China.
  • 3 School of Medicine, Shenzhen University, Shenzhen 518060, Guangdong, PR China.
  • 4 Hunan Qianjin Xiangjiang Pharmaceutical Co., Ltd, Changsha 410013, Hunan, PR China.
  • 5 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China; Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha 410013, Hunan, PR China.
  • 6 Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou, PR China.
  • 7 Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, PR China. Electronic address: qbli@csu.edu.cn.
PMID: 30777660 DOI: 10.1016/j.bmc.2019.01.028
Abstract

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective Cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 Inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung Cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and Akt in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung Cancer therapy.

Keywords

5-(Phenylamino) indolone; Dual inhibitor; Lung cancer; PI3K-PDK1-AKT pathway; RAF-MEK-ERK pathway; Structure-activity relationship.

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