The ubiquitination status is tightly regulated at both the ubiquitination level by the E1, E2, and E3 ubiquitin ligase system and the deubiquitination level by over 90 deubiquitinases (DUBs). USP2 (ubiquitin specific peptidase 2) is a DUB that removes ubiquitin thereby stabilizing a range of substrates, including MDM2 (a regulator of p53), fatty-acid synthase, cyclin D1, and proteins important for the circadian rhythm, such as CRY1[2]. ML364 is a small molecule inhibitor of the deubiquitinase USP2 with an IC50 value of 1.1 μM[2]. ML364 (5-20 μM; 24-48 hours) inhibits LnCAP and MCF7 cells viability in a dose-dependent manner and ML364 (10 μM; 2-24 hours) reduces cyclin D1 protein levels in a time-, dose-, and proteasome-dependent manner in HCT116 cells and Mino cells[2]. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest utilizing both Mino and HCT116 cancer cell lines. As mitotic arrest is poorly tolerated by cancer cells, viability was decreased in multiple cancer cell lines upon treatment with ML364. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination-mediated DNA repair[2]. Besides, ML364 increases the levels of mitochondrial ROS and decreases in the intracellular content of ATP[3].
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