It has been reported that sodium iodide symporter is transmembrane glycoprotein and induce an iodide uptake in thyroid follicular cell. Radioiodine therapy and nuclear medicine imaging with sodium iodide symporter (NIS) has been widely used in clinical setting for treatment and diagnosis of well differentiated thyroid cancer and their metastasis with minimal adverse effects. But, its practical application to anaplastic thyroid cancer (ATC) of poorly differentiated thyroid cancer exhibiting a progressive dedifferentiation with resistance to cancer treatments and aggressive metastasis to lung, bone, and regional lymph node is impossible due to insufficient expression and function of NIS. Thus, new strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogenrelated receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μM), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC.