The application of advanced liver spheroid assay to small molecule lead optimization -Chemical toxicology perspective-

<p>It has long been reported that toxicity in non-clinical and clinical stages is the main reason why compounds are terminated in drug development. Therefore, to increase the success rate of drug development, compound evaluation and design with a safety perspective are strongly needed from the early stage of drug discovery. A similar trend was seen in our attrition analysis. Based on the past 20 years of legacy compound analysis, hepatotoxicity and cardiotoxicity accounted for the largest proportions in that order. Therefore, we have re-built a safety screening strategy including in silico and in vitro assays, and have applied it to all small molecule projects to find risks at an early stage.</p><p>For example, in the evaluation of hepatotoxicity, compounds are first filtered out by cytotoxicity assay using HepG2 cells and then evaluated in liver spheroid prepared by primary human hepatocyte for 14 days. As a validation study, we evaluated 47 in-house compounds that were terminated due to hepatotoxicity in the non-clinical stage and found that the risk of 82% of the compounds could be detected. This analysis clearly showed the utility of our screening strategy for compound optimization. On the other hand, it is also clear that using a 14 days assay for the real-time compound design-synthesis-evaluation cycle is very difficult from the point of view of medicinal chemistry. Therefore, we investigated whether the culture time of this assay system could be shortened, and identified that similar results could be obtained even in 7 days assay. In this talk, I would like to introduce the efforts to apply the advanced in vitro model to avoid hepatotoxicity.</p>