A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma

Despite
the recent advances in cancer therapeutics, highly aggressive
cancer 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 as a novel therapeutic target in highly malignant
phenotypes including GBM. Here, we report the development of a novel,
highly potent, and metabolically stable peptide inhibitor of syntenin,
KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar
affinity. KSL-128114 is resistant toward degradation in human plasma
and mouse hepatic microsomes and displays a global PDZ domain selectivity
for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts
with syntenin PDZ1 in an extended noncanonical binding mode. Treatment
with KSL-128114 shows an inhibitory effect on primary GBM cell viability
and significantly extends survival time in a patient-derived xenograft
mouse model. Thus, KSL-128114 is a novel promising candidate with
therapeutic potential for highly aggressive tumors, such as GBM.