Key result
Structure-based design successfully developed non-hERG binding TLR7/9 antagonists with IC50 >30 μM while retaining antagonism through a single point change in the scaffold.
Why the study?
Most lead quinazoline-based TLR7 and TLR9 antagonists suffer from hERG liability that renders them ineffective for further development.
Population
Quinazoline-based TLR7 and TLR9 antagonists
Comparison
Single point change in the scaffold vs original lead antagonists
Design
Preclinical structure-guided lead optimization study
Authors
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May enable safer TLR7/9 antagonist leads; leaves open translation to human trials.
Structure-based design can successfully eliminate hERG liability in TLR7/9 antagonists while maintaining target potency, providing a prototype for early-stage drug optimization.
Das et al. (2023) studied Autoimmune disease. Structure-based design of quinazoline-based TLR7 and TLR9 antagonists was evaluated on hERG binding (IC50). Structure-based design successfully developed non-hERG binding TLR7/9 antagonists with IC50 >30 μM while retaining antagonism through a single point change in the scaffold.
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