Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Kim, Byung Hak; Lee, Haeri; Song, Yeonghun; Park, Joon Suk; Gadhe, Changdev G.; Choi, Jiwon; Lee, Chung Gi; Pae, Ae Nim; Kim, Sanghee; Ye, Sang Kyu

doi:10.3390/jcm8111847

Cited by 17 publications

(15 citation statements)

References 49 publications

(85 reference statements)

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“…Our previous study has shown that ODZ10117 is a novel small molecule compound of STAT3 inhibitor [15]. In this study, we further demonstrated the valuable therapeutic efficacy of ODZ10117 in both in vitro and in vivo models of glioblastoma and GSCs.…”

Section: Discussionsupporting

confidence: 61%

“…We previously reported that oxadiazole-based small molecule 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl- [1,2,4]oxadiazole (ODZ10117) is a direct inhibitor of STAT3 by targeting the SH2 domain of STAT3 [15]. In the present study, we demonstrated the pharmacological effect of ODZ10117 in both in vitro and in vivo models of glioblastoma and glioblastoma cancer stem cells (GSCs).…”

Section: Introductionmentioning

confidence: 62%

“…Glioblastoma is the most incurable type of cancer with few therapeutic options, and STAT3 is a promising therapeutic target for glioblastoma [4,22]. ODZ10117 was previously reported as a direct inhibitor of STAT3 by targeting the SH2 domain of STAT3 [15]. Therefore, we investigated whether ODZ10117 may affect STAT3 activation in glioblastoma and primary glioblastoma cells.…”

Section: Odz10117 Inhibits Stat3 Activation In Glioblastoma Cellsmentioning

confidence: 98%

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STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model

Kim

Lee

Park

et al. 2020

Cells

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Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 62%

Section: Odz10117 Inhibits Stat3 Activation In Glioblastoma Cellsmentioning

confidence: 98%

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STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model

Kim

Lee

Park

et al. 2020

Cells

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“…5 Moreover, it has been demonstrated that PIM inhibitors can enhance the efficacy of existing PCa treatments, which will be discussed further, including radiotherapy, 10 chemotherapy, 9 and androgen deprivation. 59 PIM co-targeting could also reduce patient mortality by potentiating the antimetastatic effects of other treatments, including strategies targeting the PI3K pathway 60,61 or JAK/STAT pathway 62,63 or anti-androgen therapy. 64 PIM AND THE PI3K PATHWAY The PI3K/AKT/mTOR pathway has been shown to contribute to the development of all hallmarks of cancer and is frequently disrupted in cancer.…”

Section: Pim Inhibition Within the Prostate Cancer Clinical Pathwaymentioning

confidence: 99%

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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“…Several structural derivatives of oxadiazole have been studied extensively for their cytotoxic activity and shown to possess potent anticancer activity in a wide range of cancer cells [ 33 , 34 ]. Recently, ODZ10117, a 1,2,4-oxadiazole derivative, was identified as the direct inhibitor of STAT3 using structure-based computational database screening and cell-based high-throughput screening [ 35 ]. ODZ10117 was reported to induce potent anticancer activity in breast cancer preclinical models by targeting the SH2 domain of the STAT3 [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

et al. 2020

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Lung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles were synthesized and examined for their anticancer potential in a panel of cancer cell lines. Among the new compounds, 2-(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (CHK9) showed consistently good cytotoxicity towards lung cancer cells with IC50 values ranging between 4.8–5.1 µM. The proapoptotic effect of CHK9 was further demonstrated by Annexin-FITC staining and TUNEL assay. In addition, the effect of CHK9 on the activation of STAT3 in lung cancer cells was examined. CHK9 reduced the phosphorylation of STAT3Y705 in a dose-dependent manner. CHK9 had no effect on the activation and expression of JAK2 and STAT5. It also reduced the STAT3-dependent luciferase reporter gene expression. CHK9 increased the expression of proapoptotic (p53 and Bax) proteins and decreased the expression of the antiapoptotic (Bcl-2, Bcl-xL, BID, and ICAM-1) proteins. CHK9 displayed a significant reduction in the number of tumor nodules in the in vivo lung cancer model with suppression of STAT3 activation in tumor tissues. CHK9 did not show substantial toxicity in the normal murine model. Overall, CHK9 inhibits the growth of lung cancer cells and tumors by interfering with the STAT3 signaling pathway.

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Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

Cited by 17 publications

References 49 publications

STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model

STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

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