MDA-9/Syntenin small molecule inhibitor IVMT-Rx-4 blocks prostate cancer bone metastasis

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). This process originates through an interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche. Melanoma differentiation associated gene-9 ( mda-9/Syntenin ) is a pro-metastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. MDA-9/Syntenin coordinates the interactions between tumor cells and BM-MSCs, which promote establishment of metastatic tumors in the bone niche. Considering the importance of protein-protein interactions in regulating MDA-9/Syntenin functions, we focused on developing small molecule inhibitors of these interactions. We describe the translational potential of IVMT-Rx-4, an intermediate synthesis product of PDZ1i, in inhibiting PC bone metastasis. IVMT-Rx-4 has similar bioactivity as PDZ1i but with improved druggable properties, e.g., higher solubility and lower efflux. It promotes potent anti-invasive and anti-metastatic effects by inhibiting the MDA-9/Syntenin dependent tumor-derived platelet derived growth factor, PDGF-AA, and its related signalling in BM-MSCs. In addition, the combination of IVMT-Rx-4 and docetaxel enhances survival in experimental bone metastasis models. These observations reinforce the concept that together with metastasis suppression, IVMT-Rx-4 can boost the effectiveness of standard-of-care treatment. Collectively, the present work provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC. • Developing effective therapies for prostate cancer bone metastasis, a final stage of PC progression leading to patient morbidity and without effective treatments, is a medical priority. • IVMT-Rx-4, an intermediate product of PDZ1i synthesis, surprisingly showed anti-invasive and anti-metastatic properties against PC cell lines with improved “drug-like” properties vs. PDZ1i, e.g., higher aqueous solubility, lower efflux, and a similar lack of toxicity. • IVMT-Rx-4 blocks protein-protein interactions that specifically interrupt MDA-9/Syntenin signaling, leading to an inhibition in progression of PC cells to bone metastasis. • IVMT-Rx-4 augments beneficial outcomes of docetaxel, a standard-of-care chemotherapy for advanced PC patients, in terms of promoting survival gains in both syngeneic and athymic nude mice injected with murine and human advanced PC cell lines, respectively.