Matrix metalloproteinase-9 (MMP-9) is critically involved in the tumor invasion and metastasis processes. Since TNF-alpha plays a crucial role in the regulation of MMP-9 expression, the development of molecules capable of modulating TNF-alpha-induced signaling is an issue of concern. We identified a novel synthetic compound that inhibits TNF-alpha-induced MMP-9 upregulation in the HT1080 human fibrosarcoma, cell line. The active compound SM-7368 inhibited TNF-alpha-induced MMP-9 upregulation in a concentration-dependent manner and showed maximal activity at 10 mu M. SM-7368 inhibited TNF-alpha-induced MMP-9 mRNA transcript accumulation and protein expression. We also found that SM-7368 strongly inhibits TNIF-alpha-induced NF-kappa B activity but not AP-1 activity. Moreover, we found that SM-7368 strongly inhibits the TNF-alpha-induced invasion of HT1080 human fibrosarcoma cell line. Taken together, our results demonstrate that SM-7368 is a synthetic compound that inhibits TNIF-a-induced MMP-9 expression, and thus SM-7368 should be useful for the development of chemotherapies targeting TNF-alpha-mediated,tumor invasion and metastasis. (c) 2005 Elsevier Inc. All rights reserved.