GZD824 overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo

被引：16

作者：

Jiang, Kaili ^{[1
]}

Tang, Xia ^{[1
]}

Guo, Jing ^{[1
]}

He, Rui ^{[1
]}

Chan, Shingpan ^{[1
]}

Song, Xiaojuan ^{[2
]}

Tu, Zhengchao ^{[1
,2
]}

Wang, Yuting ^{[1
]}

Ren, Xiaomei ^{[1
]}

Ding, Ke ^{[1
]}

Zhang, Zhang ^{[1
]}

机构：

[1] Jinan Univ, Int Cooperat Lab Tradit Chinese Med Modernizat &, Guangzhou City Key Lab Precis Chem Drug Dev, Chinese Minist Educ MOE,Sch Pharm, Guangzhou, Peoples R China

[2] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou, Peoples R China

来源：

CANCER MEDICINE | 2021年 / 10卷 / 14期

基金：

中国国家自然科学基金;

关键词：

FGFR1; GZD824; resistance; V561F; ACQUIRED-RESISTANCE; INHIBITOR; FGFR1; KINASE; CELL; ACTIVATION; SENSITIVITY; EXPRESSION; MUTATIONS; REVEALS;

D O I：

10.1002/cam4.4041

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC50 value of 4.14 +/- 0.96, 2.77 +/- 0.082, and 8.10 +/- 0.15 nmol/L. It effectively overcomes FGFR1-V561F/M and other mutantresistance in Ba/F3 stable cells (IC50:8.1-55.0 nM), and effectively inhibits the growth of Ba/F3-FGFR1-V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials.

引用

收藏

页码：4874 / 4884

页数：11

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