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.

Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small‐Molecule Antagonists

“…Our predicted binding mode and interaction with Arg-53 was recently independently confirmed by a crystal structure of an analog of IPR-803 bound to uPAR. [19] …”

“…Computational studies that include molecular dynamics simulations predicted ab inding mode for the compound along with ac ritical saltbridge interaction with an Arg-53 [18] residue.O ur predicted binding mode and interaction with Arg-53 was recently independently confirmed by ac rystal structure of an analogue of IPR-803 bound to uPAR. [19] Historically,m ost rational approaches for the design of small-molecule inhibitors of protein-protein interactions have focusedo nm imicking the position of amino acids located on the protein ligand of ap rotein-protein interaction. [20][21][22] Several studies have used interface residues of the protein ligand of a protein-protein interaction to guide the design of small-molecule inhibitors in virtuals creening and lead optimization.…”

Chemical Space Overlap with Critical Protein–Protein Interface Residues in Commercial and Specialized Small‐Molecule Libraries

“…In one case, we screened multiple structures that were sampled from explicit‐solvent molecular‐dynamics simulations and identified a sub‐micromolar affinity compound . The predicted structure of the compound was independently confirmed by X‐ray crystallography . More recently, we introduced a fingerprint method that uses the native protein ligand as a guide to identify small molecules that mimic the interaction of the protein ligand .…”

“…[11] The predicted structure of the compound was independently confirmed by X-ray crystallography. [14] More recently,w ei ntroducedafingerprint method that uses the native protein ligand as ag uide to identify small molecules that mimic the interaction of the protein ligand. [13] There is growing interest in the use of structure-based virtual screening to identify small molecules that inhibit challenging protein-protein interactions (PPIs).…”

Efficient Innate Immune Killing of Cancer Cells Triggered by Cell‐Surface Anchoring of Multivalent Antibody‐Recruiting Polymers

“…[8] Theo rigin of these endogenous antibodies varies from the consumption of meat (galactose-a-1,3-galactose), commensal bacteria in the gut (phosphorylcholine and rhamnose), and exposure to pesticides (DNP). This approach is intended for local application, that is,b yd irect intratumoral injection, owing to the lack of selectivity towards cancer cells.A nother strategy involves conjugates composed of an antibody-binding motif and atarget-cell-binding motif.F or the latter, several cell surface receptors that are overexpressed by cancer cells have been explored, including the folate receptor, [10] PSMA, [11] uPAR, [12] and others.T hese approaches all involve mono-or at best bivalent molecules,both on the level of the antibody-binding as well as the target-cell-binding motifs. [9] Thel ipid part anchors the cell membrane and exposes the antibody-binding motif to the external medium.…”