title: Discovery and anti-cancer evaluation of two novel non-ATP-competitive FGFR1 inhibitors in non-small-cell lung cancer.
abstract: BACKGROUND
  Fibroblast growth factor receptor 1 (FGFR1) is correlated closely with the occurrence and development of lung cancer. FGFR1 kinase inhibitors have exhibited significant therapeutic effects against non-small-cell lung cancer. Recently, non-ATP competitive FGFR1 inhibitors have attracted extensive attention due to their low side effects.
  
  
  METHODS
  Caliper Mobility Shift Assay was used for FGFR1 inhibition test and kinase inhibitory mode study. Hoechst staining and Annexin V/PI staining were used to evaluate the cell apoptosis induction. Western blot were then performed to confirm the intracellular FGFR1 inhibition and apoptotic protein expression. Finally, the anti-tumor effect and mechanism of Af23 and Ad23 was evaluated in vivo.
  
  
  RESULTS
  In this study, we designed, synthesized and discovered two novel non-ATP competitive FGFR1 inhibitors, Af23 and Ad23, using NDGA as a leading compound. They had IC50 values of 0.6 μM and 1.4 μM against FGFR1 kinase, respectively. The kinase inhibitory assay carried at different ATP concentrations showed that the FGFR1 inhibition mode of both Ad23 and Af23 was non-ATP-competitive. Further, Af23 and Ad23 significantly suppressed FGFR1 phosphorylation and cell proliferation in non-small-cell lung cancer (NSLCLC) H460 cells and induced cell apoptosis. Af23 and Ad23 also showed significant anti-tumor activity in the H460 xenograft mouse model, accompanied with the inhibition of FGFR1, ERK, and AKT phosphorylation without exhibiting toxicity.
  
  
  CONCLUSIONS
  These results indicate that Ad23 and Af23 are potential agents for the treatment of non-small-cell lung cancer. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. wujianzhang6@163.com.
authors.forename: Jianzhang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. weitao55@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. tangqinqin0203@163.com.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. 871758631@qq.com.
authors.forename: Bixia
authors.initials: B
authors.lastname: Weng
authors.affiliation: College of Information Science and Computer Engineering, Wenzhou Medical Universtiy, Wenzhou, Zhejiang, 325035, China. liwulan@163.com.
authors.forename: Wulan
authors.initials: W
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. 334555768@qq.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, the Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China. dtcjm@163.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Ding
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. proflxk@163.com.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. cuiliang1234@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. ypcai@126.com.
authors.forename: Yuepiao
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. jjctcty@sina.com.|Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China. jjctcty@sina.com.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Ji
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009637:Masoprocol / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D009637:Masoprocol; D000255:Adenosine Triphosphate; D051496:Receptor, Fibroblast Growth Factor, Type 1