Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor

被引：59

作者：

Rullo, Anthony F. ^{[1
]}

Fitzgerald, Kelly J. ^{[2
]}

Muthusamy, Viswanathan ^{[1
]}

Liu, Min ^{[3
,4
]}

Yuan, Cai ^{[3
]}

Huang, Mingdong ^{[3
]}

Kim, Minsup

Cho, Art E. ^{[4
]}

Spiegel, David A. ^{[1
,2
]}

机构：

[1] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06511 USA

[2] Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA

[3] Chinese Acad Sci, Fujian Inst Res Struct Matter, State Key Lab Struct Chem, 155 Yang Qiao West Rd, Fuzhou 350002, Peoples R China

[4] Korea Univ, Dept Bioinformat, 2511 Sejong Ro, Sejong 339700, South Korea

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 11期

关键词：

antitumor agents; cell recognition; drug design; immunology; medicinal chemistry; PLASMINOGEN-ACTIVATOR; IMMUNOTHERAPY; MICE; UPAR;

D O I：

10.1002/anie.201510866

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody-recruiting small molecule (ARM) that is capable of recognizing the urokinase-type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell-surface marker, and facilitating the immune-mediated destruction of cancer cells. A co-crystal structure of the ARM-U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non-peptide ligand. Finally, we demonstrated that ARM-U2 substantially suppresses tumor growth invivo with no evidence of weight loss, unlike the standard-of-care agent doxorubicin. This work underscores the promise of antibody-recruiting molecules as immunotherapeutics for treating cancer.

引用

页码：3642 / 3646

页数：5

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