A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Despite the recent advances in cancer therapeutics, highly aggressive forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged a novel therapeutic target malignant phenotypes including GBM. Here, we report development of novel, potent, and metabolically stable peptide inhibitor KSL-128114, which binds PDZ1 domain syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation human plasma mouse hepatic microsomes displays global PDZ selectivity for syntenin. An X-ray crystal structure reveals that interacts an extended noncanonical binding mode. Treatment shows inhibitory effect on primary GBM cell viability significantly extends time patient-derived xenograft model. Thus, promising candidate potential tumors,