Identification and characterization of highly potent and isoenzyme-selective inhibitors of Deiodinase type I via a nonradioactive high-throughput screening method

Sane R; Seyffarth C; Kleissle S; Neuenschwander M; JP von Kries; Fradrich C; Renko K; Wirth EK; Kohrle J

doi:10.1530/ey.22.3.2

3.2

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 3.2 | DOI: 10.1530/ey.22.3.2

ESPEYB25 3. Thyroid Basic Science (2 abstracts)

3.2. Identification and characterization of highly potent and isoenzyme-selective inhibitors of Deiodinase type I via a nonradioactive high-throughput screening method

Sane R , Seyffarth C , Kleissle S , Neuenschwander M , von Kries JP , Frädrich C , Renko K , Wirth EK & Köhrle J

Thyroid. 2025 May;35(5):576-589. doi: 10.1089/thy.2025.0036. PMID: 40170637

Brief Summary: This experimental study developed a nonradioactive high-throughput assay to identify type 1 deiodinase (DIO1) inhibitors, addressing the lack of selective tools to study or target DIO1 clinically. Given DIO1’s role in T3 production, selective inhibition may benefit patients with severe hyperthyroidism. Of 69,344 low-molecular-weight compounds screened, 15 were identified as novel, highly potent, and selective DIO1 inhibitors with nanomolar IC₅₀ values. Eight of these 15 also inhibited DIO1 in intact cells. This platform enables discovery of thyroid hormone metabolism modulators for research and therapy.

This study addresses a critical gap in thyroid hormone research by enabling the discovery of potent and selective inhibitors of DIO1, a key enzyme in T3 production. Until now, tools to selectively target DIO1 have been lacking, limiting the ability to study its physiological and pathological roles. By developing a scalable nonradioactive assay and identifying cell-active inhibitors, this study opens the door to targeted modulation of thyroid hormone metabolism in conditions like severe hyperthyroidism.