Structural Mechanism For Resistance To Thyroid Hormone And Drug Discovery

As an essential basic hormone,thyroid hormone(TH)is indispensable for human growth,development and metabolism.The impaired sensitivity of TH,also named as thyroid hormone resistance(RTH),leads to a range of diseases,including cancer,nonalcoholic steatohepatitis(NASH)and thyroid hormone resistance syndrome(RTH syndrome).Impairment of TH function in several aspects,including TH synthesis,activation,transportation and receptor-dependent transactivation,can eventually lead to hormone resistance and related diseases.Therefore,it not only implies the importance and urgency of the research and development of thyromimetic drugs,but also suggests that revealing the mechanism of RTH should be a high priority for clinical treatment and drug development.The majority of RTH cases are related to thyroid hormone receptor β(THRβ)mutations,and only a few RTH cases are associated with thyroid hormone receptor α(THRα)mutations or other causes.Patients with RTH suffer from goiter,mental retardation,short stature and bradycardia or tachycardia.As August of 2020,approximately 170 mutated THRβ variants and more than 20 mutated THRa variants at the amino acid level have been reported in RTH patients.The mechanism of hormone resistance caused by THRs mutations remains unclear,and currently,effective treatment for diseases caused by RTH is deficient in clinical practice.What calls for special attention is that these developing compounds need to avoid over activating THRα,which is associated with severe heart impairment.To search for new ligands for THRs,we used THRβ LBD as a bait and screened a chemical library based on AlphaScreen assay.Our research found the roxadustat,an anemia drug,as a selective ligand for THRβ.With distinct chemical scaffold from T3,roxadustat also binds to THRβ mutants with the therapeutic potential in the RTH.We have further solved the crystal structure of THRβ complexed with roxadustat,which revealed that the hydrophobic benzyl extension of roxadustat is the basis of THRβ selectivty.In this project,we further studied the mechanism of the hormone resistance for several THRβmutants and revealed structural insights of rescued mutant THRβ by the new compound.Based on structural mechanisms,we also designed several roxadustat derivatives to activate THRβ with more potency and selectivity.In summary,this research provides a novel structural template for the study ligandregulated THRβ activity,improves the theoretical basis of THRβ selectivity,and further reveals the clinical etiology of RTH caused by receptor mutants,which supports a drugdesign strategy for RTH by targeting THRβ mutants.Overall,my work will provide a mechanistic guidance and application of small molecules in treating thyroid hormone resistance.