Discovery of novel non-ATP competitive FGFR1 inhibitors and evaluation of their anti-tumor activity in non-small cell lung cancer in vitro and in vivo
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Jianzhang Wu1,*, Jiansong Ji2,*, Bixia Weng1, Peihong Qiu1, Karvannan Kanchana1, Tao Wei1, Yi Wang1, Yuepiao Cai1, Xiaokun Li1 and Guang Liang1
1 Chemical Biology Research Center , School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China
2 Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
* These Authors contributed equally to this work
Guang Liang, email:
Keywords: Fibroblast growth factor receptor 1; non-small-cell lung cancer; non-ATP competitive FGFR1 inhibitors; NDGA; Anti-cancer activity
Received: April 26, 2014 Accepted: June 18, 2014 Published: June 20, 2014
Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1`inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
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