Overcoming hERG Cardiotoxicity in Psammaplysene D via Rational Design to Discover a Safe Antifibrotic Lead

Liver fibrosis is a major global health challenge with limited treatment options. The marine natural product Psammaplysene D (PD) exhibits promising antifibrotic activity but suffers from significant hERG channel inhibition (>99% at 5 μM) and moderate pharmacokinetics. To address this cardiotoxicity, we employed rational optimization guided by computational toxicity prediction (ADMETlab 2.0), leading to the design and synthesis of derivatives and identification of compound C11. Patch-clamp studies confirmed C11 eliminated hERG liability (IC50 > 100 μM). C11 retained antifibrotic efficacy comparable to PD in liver fibrosis models with no observable toxicity. This work demonstrates successful separation of hERG toxicity from pharmacological activity, establishing C11 as a safe and effective lead candidate for hepatic fibrosis therapy.