Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy
by
Byung-Hak Kim 1,2,3,†, Haeri Lee 1,2,†, Yeonghun Song 4, Joon-Suk Park 5, Changdev G. Gadhe 6, Jiwon Choi 1, Chung-Gi Lee 3, Ae Nim Pae 6,7, Sanghee Kim 4 and Sang-Kyu Ye 1,2,8,9,*
Byung-Hak Kim 1,2,3,†, Haeri Lee 1,2,†, Yeonghun Song 4, Joon-Suk Park 5, Changdev G. Gadhe 6, Jiwon Choi 1, Chung-Gi Lee 3, Ae Nim Pae 6,7, Sanghee Kim 4 and Sang-Kyu Ye 1,2,8,9,*
1
Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
2
Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea
3
CYTUS H&B Corporation, Cheongju 28159, Korea
4
College of Pharmacy, Seoul National University, Seoul 08826, Korea
5
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
6
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea
7
Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
8
Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
9
Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally.
J. Clin. Med. 2019, 8(11), 1847; https://doi.org/10.3390/jcm8111847
Received: 27 August 2019 / Revised: 24 October 2019 / Accepted: 30 October 2019 / Published: 2 November 2019
(This article belongs to the Section Oncology)
Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.
Keywords:
3-(2,4-Dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117); STAT3; SH2 domain; targeted therapy; structure-based computational database screening; cell-based high-throughput screening
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Kim, B.-H.; Lee, H.; Song, Y.; Park, J.-S.; Gadhe, C.G.; Choi, J.; Lee, C.-G.; Pae, A.N.; Kim, S.; Ye, S.-K. Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy. J. Clin. Med. 2019, 8, 1847.
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