hERG Assay for Two Potent OSM-S Compounds

Published by MatTodd on 7 May 2012 - 1:26pm

Subject 

Results

One of the most potent compounds identified to date in the OSDD malaria project, the near-neighbour analog OSM-S-35 (ZYH3) was subjected to the hERG assay along with one of the original TCAMS GSK compounds which in this project has the tag OSM-S-5.

Raw data are here, plus spreadsheet here.

These results suggest that these compounds are "misses" in this assay, implying that they, and perhaps the series as a whole, would not have cardiac side effects as drugs.

Courtesy of Paul Willis at MMV: The human ether-a-go-go related gene (hERG) encodes a potassium channel in the heart (IKr) which is involved in cardiac repolarisation. Inhibition of the hERG channel can cause ‘QT interval prolongation’ resulting in a potentially fatal ventricular tachyarrhythmia called Torsade de Pointes. A number of drugs have been withdrawn from either the market or from late stage clinical trials due to these cardiotoxic effects, therefore it is important to identify hERG inhibitors early in drug discovery. Therefore the fact that these compounds are inactive at hERG is good news (Much is understood about the pharmacophores that hit the hERG channel so I was not expecting an issue for these compounds but it is always good to confirm).  A hERG inhibition at an early stage is not a show stopper but a clear issue that has to be addressed in the optimization process.