Mitigating hERG Liability of Toll‐Like Receptor 9 and 7 Antagonists through Structure‐Based Design

hERG is considered to be a primary anti‐target in the drug development process, as the K+ channel encoded by hERG plays an important role in cardiac re‐polarization. It is desirable to address the hERG safety liability during early‐stage development to avoid the expenses of validating leads that will eventually fail at a later stage. We have previously reported the development of highly potent quinazoline‐based TLR7 and TLR9 antagonists for possible application against autoimmune disease. Initial experimental hERG assessment showed that most of the lead TLR7 and TLR9 antagonists suffer from hERG liability rendering them ineffective for further development. The present study herein describes a coordinated strategy to integrate the understanding from structure‐based protein‐ligand interaction to develop non‐ hERG binders with IC50 >30 μM with retention of TLR7/9 antagonism through a single point change in the scaffold. This structure‐guided strategy can serve as a prototype for abolishing hERG liability during lead optimization. A coordinated strategy was taken to integrate the understanding from structure‐based protein‐ligand interactions to develop non‐hERG binders with IC50 values >30 μM while retaining TLR7/9 antagonism through a single point change in the scaffold. This structure‐guided strategy can serve as a prototype for abolishing hERG liability during lead optimization.