2. Academic Validation
  3. Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors

Design, synthesis and biological evaluation of a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent fibroblast growth factor receptor (FGFR) inhibitors

  • Eur J Med Chem. 2018 Jun 25:154:9-28. doi: 10.1016/j.ejmech.2018.05.005.
Manman Wei 1,  Xia Peng 2,  Li Xing 3,  Yang Dai 2,  Ruimin Huang 4,  Meiyu Geng 2,  Ao Zhang 5,  Jing Ai 6,  Zilan Song 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 3 CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 5 CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 6 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China. Electronic address: jai@simm.ac.cn.
  • 7 CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China. Electronic address: songalan@simm.ac.cn.
PMID: 29775937 DOI: 10.1016/j.ejmech.2018.05.005
Abstract

Starting from the phase II clinical FGFR Inhibitor lucitanib (2), we conducted a medicinal chemistry approach by opening the central quinoline skeleton coupled with a scaffold hopping process thus leading to a series of novel 2-benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives. Compound 25a was identified to show selective and equally high potency against FGFR1/2 and VEGFR2/KDR/Flk-1 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2/KDR/Flk-1 aberrant Cancer cells were observed. In the SNU-16 xenograft model, compound 25a showed tumor growth inhibition rates of 25.0% and 81.0% at doses of 10 mg/kg and 50 mg/kg, respectively, with 5% and 10%body weight loss. In view of the synergistic potential of FGFs and VEGFs in tumor angiogenesis observed in preclinical studies, the FGFR/VEGFR2/KDR/Flk-1 dual inhibitor 25a may achieve better clinical benefits.

Keywords

FGFR; Lucitanib; Synergistic effect; Tumor growth inhibition; VEGFR.

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