We aimed to discover whether enhancing NIS function by modulating proteostasis was targetable in vivo, as well as the clinical relevance to radioiodide (RAI) treatment of patients with cancer.<h4>Methods</h4>We used 3D modelling, iterative design, reformulation, RAI uptake, RNA-Seq, cell surface biotinylation assays and NanoBRET in transformed cell lines and primary thyroid cells from patients to identify new drugs targeted at enhancing NIS function and to uncover their respective mechanisms. The gene discussed is SLC5A5; the disease is cancer.