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

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 mark...

Full description

Saved in:
Bibliographic Details
Published inAngewandte Chemie Vol. 128; no. 11; pp. 3706 - 3710
Main Authors Rullo, Anthony F., Fitzgerald, Kelly J., Muthusamy, Viswanathan, Liu, Min, Yuan, Cai, Huang, Mingdong, Kim, Minsup, Cho, Art E., Spiegel, David A.
Format Journal Article
LanguageEnglish
German
Published Weinheim Blackwell Publishing Ltd 07.03.2016
Wiley Subscription Services, Inc
Subjects
Cancer
Cell surface
Chemistry
Crystal structure
Destruction
Doxorubicin
Engineering
Immune response
Immune system
Immunologie
Ligands
Markers
Medizinische Chemie
Metastases
Metastasis
Receptors
Reengineering
Strategy
Surface markers
Tumortherapeutika
U-Plasminogen activator
Urokinase
Weight loss
Wirkstoffentwicklung
Zellerkennung
Online AccessGet full text

Cover

More Information
Summary: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 in vivo 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. Ein immuntherapeutischer Ansatz mit kleinen Molekülen basiert auf der selektiven Markierung von Krebszellen zur Erkennung durch Immunzellen und gezielten Zerstörung. Diese Herangehensweise ist äußerst vielversprechend für die Behandlung von hoch aggressivem metastatischem Krebs, möglicherweise sogar mit nur geringen Nebenwirkungen.
Bibliography:istex:7CED6A2BB8B1088FBEF37D2287080CBCB44A1E1D
Bristol-Myers Squibb
ArticleID:ANGE201510866
Bristol-Myers Squibb - No. OCR4997.11
ark:/67375/WNG-89BW6HLB-B
NRF - No. 2013R1A2A2A01067638; No. 2012M3C1A6035362
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201510866