Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

被引：20

作者：

Ma, Lin ^{[1
,2
]}

Li, Yingying ^{[1
,2
]}

Luo, Ruixiang ^{[1
,2
]}

Wang, Yuhan ^{[1
,2
]}

Cao, Jiaqi ^{[1
,2
]}

Fu, Weitao ^{[3
]}

Qian, Bolan ^{[1
,2
]}

Zheng, Lei ^{[1
,2
]}

Tang, Longguang ^{[4
]}

Lv, Xinting ^{[1
,2
]}

Zheng, Lulu ^{[5
]}

Liang, Guang ^{[1
,2
]}

Chen, Lingfeng ^{[1
,2
]}

机构：

[1] Affiliated Yongkang First Peoples Hosp, Hangzhou 310012, Zhejiang, Peoples R China

[2] Hangzhou Med Coll, Sch Pharm, Hangzhou 310012, Zhejiang, Peoples R China

[3] Jiangsu Vcare PharmaTech Co Ltd, Dept Comp Aided Drug Design, Nanjing 211800, Peoples R China

[4] Zhejiang Univ, Affiliated Hosp 4, Int Inst Med, Sch Med, Hangzhou 322000, Zhejiang, Peoples R China

[5] Tongde Hosp Zhejiang Prov, Dept Pharm, Hangzhou 310000, Zhejiang, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 11期

基金：

中国国家自然科学基金;

关键词：

STRUCTURAL BASIS; INHIBITION; GROWTH; DEGRADATION; RESISTANCE; THERAPEUTICS; PEMIGATINIB; DESIGN; KLOTHO;

D O I：

10.1021/acs.jmedchem.3c00150

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Abnormalactivation of fibroblast growth factor receptors (FGFRs)results in the development and progression of human cancers. FGFR2is frequently amplified or mutated in cancers; therefore, it is anattractive target for tumor therapy. Despite the development of severalpan-FGFR inhibitors, their long-term therapeutic efficacy is hinderedby acquired mutations and low isoform selectivity. Herein, we reportthe discovery of an efficient and selective FGFR2 proteolysis-targetingchimeric molecule, LC-MB12, that incorporates an essential rigid linker.LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2among the four FGFR isoforms; this may promote greater clinical benefits.LC-MB12 exhibits superior potency in FGFR signaling suppression andanti-proliferative activity compared to the parental inhibitor. Furthermore,LC-MB12 is orally bioavailable and shows significant antitumor effectsin FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12is a candidate FGFR2 degrader for alternative FGFR2-targeting strategiesand offers a promising starting point for drug development.

引用

页码：7438 / 7453

页数：16

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