title: 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.
abstract: 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.
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China. These Authors contributed equally to this work.
authors: Jianzhang
authors: J
authors: Wu
authors: Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China. These Authors contributed equally to this work.
authors: Jiansong
authors: J
authors: Ji
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Bixia
authors: B
authors: Weng
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Peihong
authors: P
authors: Qiu
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Karvannan
authors: K
authors: Kanchana
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Tao
authors: T
authors: Wei
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Yi
authors: Y
authors: Wang
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Yuepiao
authors: Y
authors: Cai
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Xiaokun
authors: X
authors: Li
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China.
authors: Guang
authors: G
authors: Liang
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy*