title: A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: Cell 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.
authors.forename: Zhi-guang
authors.initials: ZG
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cell 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.
authors.forename: Hong-yong
authors.initials: HY
authors.lastname: Cui
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Jian-long
authors.initials: JL
authors.lastname: Peng
authors.affiliation: Cell 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.
authors.forename: Shi-jie
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Cell 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.
authors.forename: Jie-jie
authors.initials: JJ
authors.lastname: Geng
authors.affiliation: Cell 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.
authors.forename: Ji-de
authors.initials: JD
authors.lastname: Liu
authors.affiliation: Cell 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Feng
authors.affiliation: Cell 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.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Cell 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Clinical Immunology, PLA Specialized Research Institute of Rheumatology & Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Cell 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.
authors.forename: Jian-li
authors.initials: JL
authors.lastname: Jiang
authors.affiliation: Cell 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.
authors.forename: Zhi-nan
authors.initials: ZN
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D051926:Basigin / Q000187:drug effects / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051926:Basigin; D048049:Extracellular Signal-Regulated MAP Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: CD147; dimerization; hepatocellular carcinoma cells; metastasis; small molecule inhibitor