Suppression of Prostate Cancer Pathogenesis Using an MDA-9/Syntenin (SDCBP) PDZ1 Small-Molecule Inhibitor

  • Mol Cancer Ther. 2019 Nov;18(11):1997-2007. doi: 10.1158/1535-7163.MCT-18-1019.
Swadesh K Das  1  2  3 ,  Timothy P Kegelman  4 ,  Anjan K Pradhan  4 ,  Xue-Ning Shen  4 ,  Praveen Bhoopathi  4 ,  Sarmistha Talukdar  4 ,  Santanu Maji  4 ,  Devanand Sarkar  4  2  3 ,  Luni Emdad  4  2  3 ,  Paul B Fisher  1  2  3
Affiliations
  • 1. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. [email protected] [email protected].
  • 2. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 3. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
  • 4. Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
PMID: 31345950 DOI: 10.1158/1535-7163.MCT-18-1019
Abstract

Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate Cancer pathogenesis. These observations firmly established MDA-9/Syntenin as a potential molecular target in prostate Cancer. MDA-9/Syntenin contains two highly homologous PDZ domains predicted to interact with a plethora of proteins, many of which are central to the cancerous process. An MDA-9/Syntenin PDZ1 domain-targeted small molecule (PDZ1i) was previously developed using fragment-based drug discovery (FBDD) guided by NMR spectroscopy and was found to be well-tolerated in vivo, had significant half-life (t 1/2 = 9 hours) and displayed substantial anti-prostate Cancer preclinical in vivo activity. PDZ1i blocked tumor cell invasion and migration in vitro, and metastasis in vivo Hence, we demonstrate that PDZ1i an MDA-9/Syntenin PDZ1 target-specific small-molecule inhibitor displays therapeutic potential for prostate and potentially Other cancers expressing elevated levels of MDA-9/Syntenin.

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