Discovery of a Potent, Selective, and Multiple His435 Mutation-Sensitive Thyroid Hormone Receptor β Agonist

Beyond selectivity concerns for thyroid hormone receptor
β
(THR-β) agonists, intolerance to the His435 mutation remains
a challenge. Following our previous study, we performed detailed modifications
on the 7-position of isoquinoline, specifically targeting the hydrophobic
region of the THR-β ligand-binding pocket (LBP). This led to
the identification of compound 15n, which showed potent
THR-β agonistic activity (EC50: 3.2 nM), moderately
selectivity (∼10-fold), and good activation of multiple His435
mutants (EC50: 134.2 nM to 515.5 nM). Co-crystal structures
revealed that the introduction of small-volume groups into the hydrophobic
pocket of THR-β almost did not significantly displace helix
11 or helix 3, explaining why 15n can activate multiple
His435 mutants simultaneously. Multiple experiments confirmed that 15n exhibits excellent lipid metabolism, safety, and pharmacokinetic
properties. Together, 15n emerges as a potent, selective,
and His435 mutation-sensitive THR-β agonist, offering potential
for treating dyslipidemia, metabolic dysfunction-associated steatohepatitis
(MASH), or resistance to thyroid hormone (RTH).