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.
Bibliographical noteFunding Information:
This work was supported by the Lundbeck foundation (K.S.), the Swedish Research Council (L.M.H.-K.), and the National Research Foundation of Korea (W.L., NRF-2017R1A2B2008483). The work in P.Z. laboratory was supported by the National Research Agency (ANR, Investissements d’Avenir, A*MIDEX project ANR-11-IDEX-0001-02), the Fund for Scientific Research-Flanders (G.08646.15N), and the foundation ARC pour la Recherche sur le Cancer (PJA 20161204584). Raphael Leblanc is the recipient of postdoctoral fellowship of the Foundation ARC pour la Recherche sur le Cancer (PDF20151203700) and A.L.E.-J. of la Ligue contre le Cancer (France).
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery