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

Moskovich, D and Finkelshtein, Y and Alfandari, A and Rosemarin, A and Lifschytz, T and Weisz, A and Mondal, S and Ungati, H and Katzav, A and Kidron, D and Mugesh, G and Ellis, M and Lerer, B and Ashur-Fabian, O (2021) Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment. In: Oncogene, 40 (44). 6248- 6257.

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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.

Item Type:	Journal Article
Publication:	Oncogene
Publisher:	Springer Nature
Additional Information:	The copyright for this article belongs to Springer Nature.
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited:	29 Mar 2023 10:46
Last Modified:	29 Mar 2023 10:46
URI:	https://eprints.iisc.ac.in/id/eprint/81174

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