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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 40 Issue 44 Pg. 6248-6257 (11 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34556811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Enzyme Inhibitors
• Small Molecule Libraries
• iodothyronine deiodinase type III
• Iodide Peroxidase

Topics

• Animals
• Carcinoma, Ovarian Epithelial (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cystadenocarcinoma, Serous (drug therapy, enzymology, genetics, pathology)
• Down-Regulation
• Enzyme Inhibitors (administration & dosage, chemical synthesis, pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Iodide Peroxidase (antagonists & inhibitors, genetics, metabolism)
• Mice
• Molecular Mimicry
• Small Molecule Libraries (administration & dosage, chemical synthesis, pharmacology)
• Xenograft Model Antitumor Assays