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

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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Fig. 1: Kaplan–Meier analysis for DIO3 and disease markers with overall survival in HGSOC patients.
Fig. 2: Design and efficacy of novel DIO3 inhibitors in HGSOC cells.
Fig. 3: Induction of apoptosis and attenuation of cell proliferation and T3-related proteins in HGSOC cells treated with the DIO3 inhibitors.
Fig. 4: DIO3 inhibitors suppress tumor growth in HGSOC xenograft model.
Fig. 5: DIO3-silenced tumors are unaffected by the drugs.
Fig. 6: Illustration of DIO3 enzymatic activity and inhibition in cancer cells.

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Acknowledgements

The work of DM was done in partial fulfillment of the requirements for a PhD degree from the Sackler Faculty of Medicine, Tel Aviv University, Israel. OA-F and BL received support from the Israel Innovation Authority, Nofar Program for Applied Research in Academia, Ministry of Economics (Project 59435).

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DM preformed, analyzed, and interpreted the experimental data. AA, AR, and YF performed some of the methods. AW, AK, and DK assisted in the IHC assays. GM, TL, and BL designed and developed the DIO3 inhibitors. SM and HU performed enzymatic inhibition assays. OA-F designed, analyzed, and interpreted the experimental data. DM, GM, BL, ME, and OA-F wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Osnat Ashur-Fabian.

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Competing interests

BL, GM, TL, and OA-F hold a patent for DIO3 inhibitors or are involved in patent commercialization. The other authors declare no potential conflict of interest.

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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 40, 6248–6257 (2021). https://doi.org/10.1038/s41388-021-02020-z

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