Mastering hERG: Med Chem Strategies for Mitigating Cardiotoxicity Risks

In the pursuit of safer drugs medicinal chemists often face the challenge of mitigating cardiotoxicity liabilities that are linked to hERG (human Ether-à-go-go-Related Gene) ion channel inhibition.

In this Coffee Chat our team discusses some of the strategies and tactics medicinal chemists use to minimize hERG-related risks during lead optimization. They explore innovative design principles for reducing hERG affinity while maintaining on-target potency and share case studies of successful implementations. This session provides valuable insights and practical approaches to addressing hERG liabilities in your programs.

Attendees submitted questions in advance and engaged with our team in a live Q&A session. Don't miss this opportunity to learn from industry case studies that successfully mitigated hERG liabilities.

Drug Hunter Speakers:
Dennis Hu Ph.D., CEO
Dennis Koester Ph. D., Director, Industry Research and Relations
Matt Hesse Ph.D., Sr. Scientific Editor

00:00 Introduction
00:30 hERG Fundamentals, Dennis Hu
09:18 Classic Strategies for hERG, Matt Hesse
15:51 Case Studies, Dennis Koester
25:33 Q&A

For additional reading take a look at these Drug Hunter Premium articles:

Ziritaxestat: https://drughunters.com/ziritaxestat
The Galapagos team tackled a hERG issue on an ATX inhibitor program by switching from a piperidine to a piperazine significantly lowering the pKa.

JNT-517: https://drughunters.com/JNT-517
Jnana mitigated a hERG liability on an amino acid transporter program by replacing a pyridazine with a urea significantly reducing lipophilicity.

TNG348: https://drughunters.com/TNG348
In their USP1 program, the team at Tango Therapeutics addressed a hERG liability by reducing lipophilicity and lowering the pKa.

Linvencorvir: https://drughunters.com/linvencorvir
To address hERG liability with this capsid assembly modulator, the Roche team employed a zwitterion strategy by introducing a carboxylic acid. They mindfully incorporated steric hindrance around the carboxylic acid to minimize the formation of acyl glucuronides.

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Presented as part of the Drug Hunter Coffee Chat series on August 15, 2024