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Human thyroid hormone receptor alpha ligand binding domain in complex with beta-selective agonist ALG-055009
Structural highlights
DiseaseTHA_HUMAN Defects in THRA are the cause of congenital hypothyroidism non-goitrous type 6 (CHNG6) [MIM:614450. A disease characterized by growth retardation, developmental retardation, skeletal dysplasia, borderline low thyroxine levels and high triiodothyronine levels. There is differential sensitivity to thyroid hormone action, with retention of hormone responsiveness in the hypothalamic pituitary axis and liver but skeletal, gastrointestinal, and myocardial resistance.[1] FunctionTHA_HUMAN Nuclear hormone receptor. High affinity receptor for triiodothyronine. Publication Abstract from PubMedAgonists of thyroid hormone receptor beta (THR-beta) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent and selective compound ALG-055009 (14) as a potential best in class THR-beta agonist. The high metabolic stability and good permeability translated well in vivo to afford a long in vivo half-life pharmacokinetic profile with limited liability for DDI, and it overcomes certain drawbacks seen in recent clinical candidates. Discovery and Preclinical Profile of ALG-055009, a Potent and Selective Thyroid Hormone Receptor Beta (THR-beta) Agonist for the Treatment of MASH.,Vandyck K, McGowan DC, Luong XG, Stevens SK, Jekle A, Gupta K, Misner DL, Chanda S, Serebryany V, Welch M, Hu H, Lv Z, Williams C, Maskos K, Lammens A, Stoycheva AD, Lin TI, Blatt LM, Beigelman LN, Symons JA, Raboisson P, Deval J J Med Chem. 2024 Sep 2. doi: 10.1021/acs.jmedchem.4c01029. PMID:39221768[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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