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

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.
Dotan Moskovich 1 2,  Yael Finkelshtein 1 2,  Adi Alfandari 1 2,  Amit Rosemarin 1 2,  Tzuri Lifschytz 3,  Avivit Weisz 4,  Santanu Mondal 5,  Harinarayana Ungati 5,  Aviva Katzav 4,  Debora Kidron 4 6,  Govindasamy Mugesh 5,  Martin Ellis 1 6,  Bernard Lerer 3,  Osnat Ashur-Fabian 7 8
Affiliations

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. osnataf@gmail.com.
  • 8 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. osnataf@gmail.com.
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.

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