Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
As one of the new modalities, target protein degraders (TPDs), degrade intracellular target proteins are being actively researched. There are approximately 10 compounds which have entered clinical trials, but their toxicity profile in humans has not been completely clarified because most of them are in the Ph1. Since TPD shows degradation activity only when the target protein-compound-E3 ligase ternary complex is in a conformation suitable for ubiquitination, “off-target toxicity observed only in animals" and "off-target toxicity in humans which cannot be detected in animals" can occur. For the latter issue, a platform for off-target toxicity assessment using human cells is now being established, but it has not yet been developed with animal cells. Currently no specific regulatory guidance for non-clinical toxicity evaluation of TPDs. TPD has been considered as small molecules so far, therefore its toxicity package is according to ICH M3 or S9. This means that toxicity study must be conducted by using both rodent/non-rodent species. In selecting animal species, confirmation whether there is on-target degradation in the target tissue is important. However, since the detection method is western blotting or LC/MS/MS, there are large species differences in the feasibility of antibody or adequacy of protein database. Additionally, even the compounds with the similar scaffold and on-target degradation activity in human cells, it has been reported that there may be large species difference on their degradation activities of homologue proteins among species. Consequently, it is considered difficult to determine which research stage/compound is appropriate to assess the degradation and toxicity profile. In this presentation, the current status and issues of non-clinical toxicity evaluation in the drug discovery of TPDs will be summarized.
