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

European Journal of Medicinal Chemistry
Manman WeiZilan Song

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 with IC50 values less than 5.0 nM. Significant antiproliferative effects on both FGFR1/2 and VEGFR2 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 dual inhibitor 25a may achieve better clinical benefits.

Citations

Oct 28, 2018·Nature Reviews. Clinical Oncology·Masaru Katoh
Nov 5, 2019·Expert Opinion on Therapeutic Patents·Giuseppe MarsegliaRiccardo Castelli
Jan 31, 2020·Saudi Pharmaceutical Journal : SPJ : the Official Publication of the Saudi Pharmaceutical Society·Güneş Çoban, Fadime Aydın Köse
Jun 25, 2020·Current Topics in Medicinal Chemistry·Xinjia YanZhi Xu
Nov 26, 2019·European Journal of Medicinal Chemistry·Feng-Tao LiuZhi-Hao Shi
Feb 9, 2021·European Journal of Medicinal Chemistry·Qi LiangJianyou Shi
Mar 4, 2021·Cell Proliferation·Guihong LiuXiawei Wei

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