MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain

Dong Ju Son^1*, Jie Zheng^1*, Yu Yeon Jung^2*, Chul Ju Hwang¹, Hee Pom Lee¹, Ju Rang Woo³, Song Yi Baek³, Young Wan Ham⁴, Min Woong Kang⁵, Minho Shong⁵, Gi Ryang Kweon⁵, Min Jong Song⁶, Jae Kyung Jung¹, Sang-Bae Han¹, Bo Yeon Kim⁷, Do Young Yoon⁸, Bu Young Choi^9✉, Jin Tae Hong^1✉

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

✉ Corresponding authors: Jin Tae Hong, PhD, Professor, College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea. Telephone: +82-43 More

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Citation:
Son DJ, Zheng J, Jung YY, Hwang CJ, Lee HP, Woo JR, Baek SY, Ham YW, Kang MW, Shong M, Kweon GR, Song MJ, Jung JK, Han SB, Kim BY, Yoon DY, Choi BY, Hong JT. MMPP Attenuates Non-Small Cell Lung Cancer Growth by Inhibiting the STAT3 DNA-Binding Activity via Direct Binding to the STAT3 DNA-Binding Domain. Theranostics 2017; 7(18):4632-4642. doi:10.7150/thno.18630. Available from https://www.thno.org/v07p4632.htm

Abstract

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.