Abstract
Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffolding protein, MDA-9/Syntenin-1 was identified and confirmed as a suitable target uniquely involved in the multiple stages of metastasis. Recently, the first-in class PDZ1 domain inhibitor for MDA-9, PDZ1i, was identified displaying significant anti-invasion activity improving survival in an in vivo glioblastoma and in multiple metastatic cancer mouse models. Herein, we report a focused library of substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[d]thiazol-2-yl)-3-phenylurea analogs bearing 6-trifluoromethyl (3y) and 6-bromo (3aa) substituents display anti-invasion activity comparable to PDZ1i. However, compounds 3y and 3aa displayed overall decreased cancer cell selectivity and MDA-9 activity relative to PDZ1i. Nonetheless, the reported 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future development of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.