2. Academic Validation
  3. Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer

Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer

  • Cancers (Basel). 2019 May 5;11(5):627. doi: 10.3390/cancers11050627.
Yanhua Fan 1 2,  Huaiwei Ding 3,  Donghwa Kim 4,  Duc-Hiep Bach 5,  Ji-Young Hong 6,  Yongnan Xu 7,  Sang Kook Lee 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea. fanyhkyem@163.com.
  • 2 The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550014, China. fanyhkyem@163.com.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. dinghuaiwei627@163.com.
  • 4 College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea. kdh9298@gmail.com.
  • 5 College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea. bdhiep90@gmail.com.
  • 6 College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea. jyhong7876@daum.net.
  • 7 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. sklee61@snu.ac.kr.
  • 8 College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea. ynxu@syphu.edu.cn.
PMID: 31060329 DOI: 10.3390/cancers11050627
Abstract

Aberrant activation of hepatocyte growth factor (HGF)/c-Met signaling pathway caused by gene amplification or mutation plays an important role in tumorigenesis. Therefore, c-Met is considered as an attractive target for Cancer therapy and c-Met inhibitors have been developed with great interests. However, cancers treated with c-Met inhibitors inevitably develop resistance commonly caused by the activation of PI3K/Akt signal transduction pathway. Therefore, the combination of c-Met and PI3Kα inhibitors showed synergistic activities, especially, in c-Met hyperactivated and PIK3CA-mutated cells. In our previous study, we rationally designed and synthesized DFX117(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-N-(2-morpholinoethyl) imidazo[1,2-a]pyridine-3-carboxamide) as a novel PI3Kα selective inhibitor. Herein, the antitumor activity and underlying mechanisms of DFX117 against non-small cell lung Cancer (NSCLC) cells were evaluated in both in vitro and in vivo animal models. Concurrent targeted c-Met and PI3Kα by DFX117 dose-dependent inhibited the cell growth of H1975 cells (PIK3CA mutation and c-Met amplification) and A549 cells (KRAS mutation). DFX117 subsequently induced G0/G1 cell cycle arrest and Apoptosis. These data highlight the significant potential of DFX117 as a feasible and efficacious agent for the treatment of NSCLC patients.

Keywords

3-substituted imidazo[1,2-a]pyridine (DFX117); apoptosis; cell cycle arrest; dual inhibitor of PI3K and Met; non-small cell lung cancer (NSCLC).

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