Abstract
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.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family consisting of seven proteins in mammals: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 [1,2]
To discover small molecules that target the SH2 domain of STAT3, we prepared a 3D-structure of the SH2 domain by extracting the corresponding region from the X-ray structure of mouse STAT3, which was available from the protein data bank (PDB), entry 1BG1 [19]
We used the 3D structure of the SH2 domain of STAT3 (PDB ID: 1BG1) and selected the coordinate from the complex structure of STAT3-DNA (PDB: 1BG1) [19]
Summary
Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family consisting of seven proteins in mammals: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 [1,2]. STAT3 is a transcription factor that remains in the cytoplasm as an inactivated form and is expressed at a basal level under normal conditions It can be activated by the phosphorylation of tyrosine 705 residue in response to cytokines, chemokines, and growth factors through receptor- and non-receptor-associated tyrosine kinases. Persistently activated STAT3 signaling is closely associated with oncogenic signaling and is frequently observed in numerous types of cancer cells and tumor tissues of cancer patients [1,5] This signaling is positively correlated with cancer aggressiveness, malignancy, recurrence, drug resistance, and a poor prognosis via promoting the survival, proliferation, invasion, and metastasis of cancer cells and maintaining cancer stem cell (CSC) properties [6,7,8]. Targeting persistently activated STAT3 signaling is considered one of the important therapeutic options for cancer treatment
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