DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo

• 作者: Meng-di Dai Yue-liang Wang Jun Fan Yang Dai Yin-chun Ji Yi-ming Sun Xia Peng Lan-lan Li Yu-ming Wang Wen-hu Duan Jian Ding Jing Ai
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（9）
• 所属期刊栏目: Chemotherapy
• 页码范围: 1498-1506
• 页数: 9页
• 语种: 英文

摘要

Fibroblast growth factor receptor (FGFR) is a promising anticancer target.Currently,most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR),limiting their feasibility due to the serious side effects.Notably,compensatory activation occurs among FGFR1-4,suggesting the urgent need to develop selective pan-FGFR1-4 inhibitors.Here,we explored the antitumor activity of DW14383,a novel irreversible FGFR1-4 inhibitor.DW14383 exhibited equivalently high potent inhibition against FGFR1,2,3 and 4,with IC50 values of less than 0.3,1.1,less than 0.3,and 0.5 nmol/L,respectively.It is a selective FGFR inhibitor,exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR,making it one of the most selective FGFR inhibitors over KDR described to date.Furthermore,DW14383 significantly inhibited cellular FGFR1-4 signaling,inducing G1/S cell cycle arrest,which in turn antagonized FGFR-dependent tumor cell proliferation.In contrast,DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration,further confirming its selectivity against FGFR.In representative FGFR-dependent xenograft models,DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling.In summary,DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers,which has the potential to overcome compensatory activation among FGFR1-4.