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Moskovich D, Finkelshtein Y, Alfandari A, et al. Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment. Oncogene. 2021;40(44):6248-6257doi: 10.1038/s41388-021-02020-z.
Moskovich, D., Finkelshtein, Y., Alfandari, A., Rosemarin, A., Lifschytz, T., Weisz, A., Mondal, S., Ungati, H., Katzav, A., Kidron, D., Mugesh, G., Ellis, M., Lerer, B., & Ashur-Fabian, O. (2021). Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment. Oncogene, 40(44), 6248-6257. https://doi.org/10.1038/s41388-021-02020-z
Moskovich, Dotan, et al. "Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment." Oncogene vol. 40,44 (2021): 6248-6257. doi: https://doi.org/10.1038/s41388-021-02020-z
Moskovich D, Finkelshtein Y, Alfandari A, Rosemarin A, Lifschytz T, Weisz A, Mondal S, Ungati H, Katzav A, Kidron D, Mugesh G, Ellis M, Lerer B, Ashur-Fabian O. Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment. Oncogene. 2021 Nov;40(44):6248-6257. doi: 10.1038/s41388-021-02020-z. Epub 2021 Sep 23. PMID: 34556811.
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Oncogene. 2021 Nov;40(44):6248-6257. doi: 10.1038/s41388-021-02020-z. Epub 2021 Sep 23.

Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment.

Oncogene

Dotan Moskovich, Yael Finkelshtein, Adi Alfandari, Amit Rosemarin, Tzuri Lifschytz, Avivit Weisz, Santanu Mondal, Harinarayana Ungati, Aviva Katzav, Debora Kidron, Govindasamy Mugesh, Martin Ellis, Bernard Lerer, Osnat Ashur-Fabian

Affiliations

  1. Translational Oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel.
  2. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  3. Biological Psychiatry Laboratory Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
  4. Department of Pathology, Meir Medical Center, Kfar Saba, Israel.
  5. Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India.
  6. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  7. Translational Oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel. [email protected].
  8. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. [email protected].

PMID: 34556811 DOI: 10.1038/s41388-021-02020-z

Abstract

The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (OVCAR3 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and OVCAR3 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian cancer and potentially other DIO3-dependent malignancies.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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