First-in-class DIO3 inhibitor as a novel treatment strategy in ovarian cancer.

3101 Background: Ovarian cancer carries high mortality, driven in part by platinum resistance and a scarcity of actionable therapeutic targets. Thyroid hormone signaling via triiodothyronine (T3) exerts tumor-suppressive effects, including inhibition of proliferative and DNA-damage stress pathways. Iodothyronine deiodinase type 3 (DIO3) is a clinically expressed T3-inactivating enzyme associated with aggressive disease biology, therapeutic resistance, and poor patient outcomes. DioTree Ltd is the first biotech company that developed ITYR-DBRMD, a first-in-class small-molecule DIO3 inhibitor for cancer treatment. Methods: DIO3 target engagement was evaluated using enzymatic mimic assays, intracellular T3 quantification (ELISA), and cellular thermal shift assays (CETSA). Pharmacokinetics (PK) were characterized across clinically relevant delivery routes (IV, IP, SC) with development of a dedicated bioanalytical quantification method. Antitumor efficacy was tested in nude mice bearing homologous recombination-proficient (HRP), carboplatin-resistant ovarian cancer xenografts. Mice received vehicle, ITYR-DBRMD, carboplatin, or their combination for three weeks. Tumor growth inhibition (TGI) and safety were assessed. Results: ITYR-DBRMD achieved selective and durable inhibition of DIO3 activity with direct cellular binding confirmation, robust increases in intracellular T3 levels, and consistent PK exposure across all administration routes tested. Monotherapy TGI was 43% for carboplatin and 50% for ITYR-DBRMD. Combination therapy produced a clinically meaningful efficacy increase, reaching 68% TGI, with no observed treatment-related toxicity or weight loss, supporting a favorable therapeutic index. Albumin-based tumor delivery and drug retention in tumors was established. Conclusions: These data support advancement of ITYR-DBRMD toward early-phase clinical testing, with potential application in ovarian cancer patients, a population lacking targeted therapeutic options.