The urokinase receptor (uPAR) is a cell-surface receptor that engages several proteins through transient and tight protein-protein interactions. As a result, a diverse set of cellular processes that include cell adhesion, migration and invasion are implicated with the receptor. Here, a substructure search of commercial libraries based on the core of previously-identified pyrazole-based compounds led to 1  (IPR-993). The pyrrolone-based compound inhibited binding of uPAR to its high-affinity serine proteinase ligand the amino-terminal fragment of the urokinase-type plasminogen activator (uPAATF) with an IC50 of 44 �M. Further substructure search of more than 500 derivatives led to derivatives 2  (IPR-1109) and 3  (IPR-1110) with IC50 of 25 and 17 �M, respectively. Synthesis of additional derivatives through modifications of the substituents on the pyrrolone core resulted in new inhibitor with higher inhibition. A structure-activity analysis provided deeper insight into the properties of the binding sites they occupy. The data guided computational studies that predicted the binding mode of the compound. In cancer cells, IPR-993 impaired breast MDA-MB-231 and pancreatic PANC-1 invasion in a concentration-dependent manner without exhibiting any cytotoxicity.

Structure-activity study of a new class of inhibitors of the uPAR-uPA protein-protein interaction that impair breast cancer cell invasion

246th National Meeting (2013)

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