The discovery of potent USP2/USP8 dual-target inhibitors for the treatment of breast cancer via structure guided optimization of ML364

In this study, we developed a series of ML364 derivatives using ligand-based drug design strategies. The standout compound, LLK203, demonstrated enhanced inhibitory activity, showing a 4-fold increase against USP2 and a 9-fold increase against USP8, compared to the parent molecule. In MCF-7 breast cancer cells, LLK203 effectively degraded key proteins involved in cancer progression and notably inhibited cell proliferation. Moreover, LLK203 exhibited potent in vivo efficacy in the 4T1 homograft model, while maintaining a low toxicity profile. These results underscore the potential of LLK203 as a promising dual-target inhibitor of USP2/USP8 for breast cancer treatment.PMID:38452725 | DOI:10.1016/j.ejmech.2024.116275
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research