AC-73 is a Specific and Orally Active CD147 Dimerization Inhibitor
Posted On 2019-11-24
Hepatocellular carcinoma (HCC) is one of the most common cancers. Combating hepatocellular carcinoma invasion and metastasis has become a major desire in hepatocellular carcinoma patients. CD147 (also called EMMPRIN) is a member of the immunoglobulin superfamily. AC-73 is the first specific inhibitor of CD147. In particular, CD147 is a type I transmembrane glycoprotein. CD147 plays an important role in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma cells. These crucial roles make CD147 an attractive target for therapeutic intervention in hepatocellular carcinoma. AC-73 targets CD147 and further specifically disrupts CD147 dimerization.
Disruption of CD147 dimerization can prevent cancer metastasis effectively through attenuating MAPK activation and matrix metalloproteinase (MMP-2) induction. Especially, AC-73 reduces hepatocellular carcinoma metastasis by suppressing MMP-2 via down-regulation of the CD147/ERK1/2/STAT3 signaling pathway. Moreover, AC-73 can directly inhibit CD147 dimerization both in the prokaryotic expression system and in living cells. AC-73 decreases the motility and invasion of hepatocellular carcinoma cells by targeting CD147. AC-73 inhibits the invasion of hepatocellular carcinoma cells by reducing MMP-2 production through blocking CD147-stimulated MAPK/STAT3 signaling. Finally, AC-73 reduces hepatocellular carcinoma metastasis in vivo. AC-73 reduces tumor metastasis by affecting the CD147/ERK1/2/STAT3 pathways. AC-73 attenuates progression in an orthotopic nude mouse model of liver metastasis. Particularly, AC-73 is relatively safe, specific for its binding target and well-tolerated in vivo. AC-73 presents low toxicity in nude mice.
All in all, CD147 has many characteristics of an ideal cancer target and plays an important role in cancer. AC-73 inhibits hepatocellular carcinoma mobility and invasion by disrupting CD147 dimerization. AC-73 is the first small-molecule inhibitor targeting CD147 that may be used as a potential intervention for hepatocellular carcinoma metastasis.