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

Anthony F Rullo; Kelly J Fitzgerald; Viswanathan Muthusamy; Min Liu; Cai Yuan; Mingdong Huang; Minsup Kim; Art E Cho; David A Spiegel

doi:10.1002/anie.201510866

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

Angew Chem Int Ed Engl. 2016 Mar 7;55(11):3642-6. doi: 10.1002/anie.201510866. Epub 2016 Feb 16.

Authors

Anthony F Rullo¹, Kelly J Fitzgerald², Viswanathan Muthusamy¹, Min Liu³, Cai Yuan³, Mingdong Huang³, Minsup Kim⁴, Art E Cho⁴, David A Spiegel^{5

6}

Affiliations

¹ Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.
² Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
³ State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yang Qiao West Road, Fuzhou, Fujian, 350002, China.
⁴ Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong, 339-700, Korea.
⁵ Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA. david.spiegel@yale.edu.
⁶ Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. david.spiegel@yale.edu.

Abstract

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.

Keywords: antitumor agents; cell recognition; drug design; immunology; medicinal chemistry.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies / immunology*
Crystallography, X-Ray
Humans
Neoplasm Metastasis / immunology*
Neoplasms / pathology
Urokinase-Type Plasminogen Activator / metabolism*

Substances

Antibodies
Urokinase-Type Plasminogen Activator

Abstract

Publication types

MeSH terms

Substances

Grants and funding