The early and costly attrition of candidate drugs for safety reasons, coupled with the rapid ascent and attractiveness of biologics and new modalities, elevates the importance of proactively engineering safety into the design of small molecules.<br/><br/>At Takeda, the Chemical Toxicology Group is not only tasked with providing project teams with an assessment of toxicological risk for the chemical space within which they reside, but to influence the direction of drug design so that safety liabilities are mitigated prior to compound nomination. This is made possible through the application of an evidence-based safety screening strategy that has been validated using compound test sets that are mechanistically relevant to the toxicological endpoint being modelled and which are applicable to modern chemical space.<br/><br/>It has been learnt that the traditional validation datasets of new assays, which often contain toxicologically potent drugs such as doxorubicin, cisplatin and sunitinb, can be useful in that they provide information on the clinical and human relevance of an assay. Often, however, they do not provide sufficient evidence, on their own, to warrant the inclusion of an assay in a predictive, risk assessment paradigm. Utility and ‘added value’ can be shown by demonstrating that an assay can differentiate the toxicological potencies of structurally-similar compounds from the same project; thus reflecting the situation that is often encountered in early drug discovery. Such robust validation studies provide the valuable evidence that helps drive the ‘Safety By Design’ concept and the development of cost-effective, risk assessment strategies. The current early safety screening strategy at Takeda will be discussed along with the validation of the component assays and its application to two recent small molecule projects.

Strategies towards the design of safer compounds at Takeda and lessons learned

2019 Fall National Meeting

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