1. Academic Validation
  2. Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis

Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis

  • Mol Cancer Ther. 2023 Oct 2;22(10):1115-1127. doi: 10.1158/1535-7163.MCT-22-0653.
Anjan K Pradhan # 1 2 Jinkal Modi # 1 Santanu Maji 1 Amit Kumar 1 Praveen Bhoopathi 1 2 Padmanabhan Mannangatti 1 2 Chunqing Guo 1 2 3 Daniel K Afosah 4 Mark C Mochel 5 Nitai D Mukhopadhyay 6 John M Kirkwood 7 Xiang-Yang Wang 1 2 3 Umesh R Desai 4 Devanand Sarkar 1 2 3 Luni Emdad 1 2 3 Swadesh K Das 1 2 3 Paul B Fisher 1 2 3
Affiliations

Affiliations

  • 1 Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 2 VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 3 VCU Institute of Molecular Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.
  • 5 Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 6 Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia.
  • 7 Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
  • # Contributed equally.
Abstract

Genome-wide gene expression analysis and animal modeling indicate that melanoma differentiation associated gene-9 (mda-9, Syntenin, Syndecan binding protein, referred to as MDA-9/Syntenin) positively regulates melanoma metastasis. The MDA-9/Syntenin protein contains two tandem PDZ domains serving as a nexus for interactions with multiple proteins that initiate transcription of metastasis-associated genes. Although targeting either PDZ domain abrogates signaling and prometastatic phenotypes, the integrity of both domains is critical for full biological function. Fragment-based drug discovery and NMR identified PDZ1i, an inhibitor of the PDZ1 domain that effectively blocks Cancer invasion in vitro and in vivo in multiple experimental animal models. To maximize disruption of MDA-9/Syntenin signaling, an inhibitor has now been developed that simultaneously binds and blocks activity of both PDZ domains. PDZ1i was joined to the second PDZ binding peptide (TNYYFV) with a PEG linker, resulting in PDZ1i/2i (IVMT-Rx-3) that engages both PDZ domains of MDA-9/Syntenin. IVMT-Rx-3 blocks MDA-9/Syntenin interaction with Src, reduces NF-κB activation, and inhibits MMP-2/MMP-9 expression, culminating in repression of melanoma metastasis. The in vivo antimetastatic properties of IVMT-Rx-3 are enhanced when combined with an immune-checkpoint inhibitor. Collectively, our results support the feasibility of engineering MDA-9 dual-PDZ inhibitors with enhanced antimetastatic activities and applications of IVMT-Rx-3 for developing novel therapeutic strategies effectively targeting melanoma and in principle, a broad spectrum of human cancers that also overexpress MDA-9/Syntenin.

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