Discussion

At AstraZeneca the Safety Screening Centre (SSC) has been established to detect safety liabilities within lead series’ chemistry throughout Discovery. Safety-related attrition remains a concern during drug discovery.

Cardiac contractility is an essential component of the heart beat, drug-induced changes in heart rhythm are associated with risk to patients and are a major cause of project failure in drug development. The current best practice methods for identifying this liability pre-clinically are in vivo canine cardiac monitoring, and ex vivo electrophysiology using explanted primary cardiac cells. These methods are low throughput, costly and typically applied to candidate drug molecules late in the discovery process. To address these issues and enable an earlier detection of liability, a screen was developed that enabled identification of pharmaceutical compounds with a propensity to affect cardiac contractility. This in vitro screen utilised FLIPR technology to identify Calcium transients (peak counts (PC) and amplitudes (PA)) which are directly related to contraction in spontaneously beating human immortalised pluripotent stem cell-derived (hiPSC) cardiomyocytes.

This built on previous publications which showed the potential of these cells to predict cardiac contractility effects similar to that of the best practice methods. Further refinements to this method delivered a routine screen with minimised compound requirement (500-fold volume reduction by acoustic dispensing) and resource (35% increased compound density per plate and elimination of out-of-hours working) whilst retaining correlation to cardiac contractility. This screen has also proven sufficiently flexible to enable customised bespoke screening of high concentration, low solubility or complex organic molecules. Significantly, introduction of this screen has enabled a reduction in use of up to 25 animals per year (3R’s).