Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

Abstract

The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound 16g, which is a potent TRβ agonist (EC 50 : 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβ H435R mutant. Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. 16g also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g is a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).

Anti-malarial activity of HCl salt of SKM13 (SKM13-2HCl)

“…To analyze PK properties, ICR mice were provided by Orient, South of Korea as previously described ( Li et al, 2022 ) and kept at an institutional animal facility under specific-pathogen-free (SPF) conditions with temperatures of ∼18–23 °C and 40–60% humidity during the experiment. They were fasted overnight and allowed free access to water before administration.…”

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

“…The recent agonists exhibit advantages in THRα/β subtype selectivity. The only amino acid difference in ligand-binding pockets between THRα and THRβ accounts for the suboptimal subtype selectivity of previous THRβ agonists [ 67 ], thereby increasing the adverse effects in heart and bone by activation of THRα [ 68 ]. The optimized compounds are designed based upon the crystal structure between THRβ and the analog of MGL-3196.…”

“…Recently, an alternative novel strategy breaks the “His-Phe switch”. A series of (4-hydroxy-1-alkoxyisoquino- line-3-carbonyl) glycine derivatives generate the potent THRβ agonist with EC 50 at 21.0 nM [ 67 ]. It shows excellent metabolic stability and pharmacokinetic profile ex vivo ( Fig.…”

Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta

“…Recently, Xu and co-workers discovered a TRβ agonist, 16g, which is sensitive to the H435R mutation ( Figure 1 ). 21 However, the impact of TRβ mutations on the activity of MGL-3196 has not been systematically studied despite its effectiveness in clinical trials.…”