Research Papers:

A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells

Zhi-guang Fu, Li Wang, Hong-yong Cui, Jian-long Peng, Shi-jie Wang, Jie-jie Geng, Ji-de Liu, Fei Feng, Fei Song, Ling Li, Ping Zhu, Jian-li Jiang and Zhi-nan Chen _

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Oncotarget. 2016; 7:9429-9447. https://doi.org/10.18632/oncotarget.6990

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Zhi-guang Fu1,*, Li Wang2,*, Hong-yong Cui1,*, Jian-long Peng3, Shi-jie Wang1, Jie-jie Geng1, Ji-de Liu1, Fei Feng1, Fei Song1, Ling Li1, Ping Zhu4, Jian-li Jiang1, Zhi-nan Chen1

1Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an, P.R. China

2State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi’an, P.R. China

3Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China

4Department of Clinical Immunology, PLA Specialized Research Institute of Rheumatology & Immunology, Xijing Hospital, Fourth Military Medical University, Xi’an, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Zhi-Nan Chen, e-mail: [email protected]

Jian-Li Jiang, e-mail: [email protected]

Keywords: CD147, small molecule inhibitor, hepatocellular carcinoma cells, metastasis, dimerization

Received: July 21, 2015    Accepted: January 17, 2016    Published: January 23, 2016


CD147, a type I transmembrane glycoprotein, is highly expressed in various cancer types and plays important roles in tumor progression, especially by promoting the motility and invasion of hepatocellular carcinoma (HCC) cells. These crucial roles make CD147 an attractive target for therapeutic intervention in HCC, but no small-molecule inhibitors of CD147 have been developed to date. To identify a candidate inhibitor, we used a pharmacophore model derived from the structure of CD147 to virtually screen over 300,000 compounds. The 100 highest-ranked compounds were subjected to biological assays, and the most potent one, dubbed AC-73 (ID number: AN-465/42834501), was studied further. We confirmed that AC-73 targeted CD147 and further demonstrated it can specifically disrupt CD147 dimerization. Moreover, molecular docking and mutagenesis experiments showed that the possible binding sites of AC-73 on CD147 included Glu64 and Glu73 in the N-terminal IgC2 domain, which two residues are located in the dimer interface of CD147. Functional assays revealed that AC-73 inhibited the motility and invasion of typical HCC cells, but not HCC cells that lacked the CD147 gene, demonstrating on-target action. Further, AC-73 reduced HCC metastasis by suppressing matrix metalloproteinase (MMP)-2 via down-regulation of the CD147/ERK1/2/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Finally, AC-73 attenuated progression in an orthotopic nude mouse model of liver metastasis, suggesting that AC-73 or its derivatives have potential for use in HCC intervention. We conclude that the novel small-molecule inhibitor AC-73 inhibits HCC mobility and invasion, probably by disrupting CD147 dimerization and thereby mainly suppressing the CD147/ERK1/2/STAT3/MMP-2 pathways, which are crucial for cancer progression.

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