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Theranostics 2017; 7(18):4632-4642. doi:10.7150/thno.18630 This issue Cite
Research Paper
1. College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea;
2. Department of Dental Hygiene, Gwangyang Health Sciences University, Gwangyang, Jeonnam 57764, Korea;
3. New Drug Development Center, Osong Medical Innovation Foundation, Cheongju, Chungbuk 28160, Republic of Korea;
4. Department of Chemistry, Utah Valley University, 800 W University Pkwy, Orem, UT 84058, USA;
5. Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Chungnam 34134, Republic of Korea;
6. Department of Obstetrics and Gynecology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, Republic of Korea;
7. World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28116, Republic of Korea;
8. Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea;
9. Department of Pharmaceutical Science and Engineering, Seowon University, Cheongju, Chungbuk, 28674, Republic of Korea.
* These authors contributed equally to this work
Rationale: Signal transducer and activator of transcription-3 (STAT3) plays a pivotal role in cancer biology. Many small-molecule inhibitors that target STAT3 have been developed as potential anticancer drugs. While designing small-molecule inhibitors that target the SH2 domain of STAT3 remains the leading focus for drug discovery, there has been a growing interest in targeting the DNA-binding domain (DBD) of the protein.
Methods: We demonstrated the potential antitumor activity of a novel, small-molecule (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) that directly binds to the DBD of STAT3, in patient-derived non-small cell lung cancer (NSCLC) xenograft model as well as in NCI-H460 cell xenograft model in nude mice.
Results: MMPP effectively inhibited the phosphorylation of STAT3 and its DNA binding activity in vitro and in vivo. It induced G1-phase cell cycle arrest and apoptosis through the regulation of cell cycle- and apoptosis-regulating genes by directly binding to the hydroxyl residue of threonine 456 in the DBD of STAT3. Furthermore, MMPP showed a similar or better antitumor activity than that of docetaxel or cisplatin.
Conclusion: MMPP is suggested to be a potential candidate for further development as an anticancer drug that targets the DBD of STAT3.
Keywords: (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol, STAT3, DNA-binding domain, anticancer, NSCLC.