title: Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor.
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.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Rullo
authors.affiliation: Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Fitzgerald
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Muthusamy
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Cai
authors.initials: C
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Mingdong
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong, 339-700, Korea.
authors.forename: Minsup
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong, 339-700, Korea.
authors.forename: Art E
authors.initials: AE
authors.lastname: Cho
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA. david.spiegel@yale.edu.|Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA. david.spiegel@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Spiegel
mesh_terms: D000906:Antibodies / Q000276:immunology*; D018360:Crystallography, X-Ray; D006801:Humans; D009362:Neoplasm Metastasis / Q000276:immunology*; D009369:Neoplasms / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D000906:Antibodies; D014568:Urokinase-Type Plasminogen Activator
keywords: antitumor agents; cell recognition; drug design; immunology; medicinal chemistry