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

1
College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea
2
The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550014, China
3
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work and shared first authorship.
Cancers 2019, 11(5), 627; https://doi.org/10.3390/cancers11050627
Received: 8 April 2019 / Revised: 26 April 2019 / Accepted: 1 May 2019 / Published: 5 May 2019
(This article belongs to the Special Issue Apoptosis in Cancer)
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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. View Full-Text
Keywords: dual inhibitor of PI3K and Met; 3-substituted imidazo[1,2-a]pyridine (DFX117); cell cycle arrest; apoptosis; non-small cell lung cancer (NSCLC) dual inhibitor of PI3K and Met; 3-substituted imidazo[1,2-a]pyridine (DFX117); cell cycle arrest; apoptosis; non-small cell lung cancer (NSCLC)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Fan, Y.; Ding, H.; Kim, D.; Bach, D.-H.; Hong, J.-Y.; Xu, Y.; Lee, S.K. Antitumor Activity of DFX117 by Dual Inhibition of c-Met and PI3Kα in Non-Small Cell Lung Cancer. Cancers 2019, 11, 627.

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