Small-Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells


Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types, including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin-specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a ubiquitin-rhodamine–based high-throughput screening, we identified small-molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the high nanomolar range. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth of leukemic cell lines in a dose-dependent manner. A known USP1 inhibitor, pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells. In addition, the growth of primary acute myelogenous leukemia (AML) patient-derived leukemic cells was inhibited by a USP1 inhibitor. Collectively, these results indicate that the novel small-molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy. Mol Cancer Ther; 12(12); 2651–62. ©2013 AACR.



USP1, ID1, small molecule inhibitors, leukemia


Copyright 2013 Molecular Cancer Therapeutics. This is a post-print version of a published paper that is available at: Recommended citation: Mistry, Helena, Grace Hsieh, Sara J. Buhrlage, Min Huang, Eunmi Park, Gregory D. Cuny, Ilene Galinsky et al. "Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells." Molecular cancer therapeutics 12, no. 12 (2013): 2651-2662.doi: 10.1158/1535-7163.MCT-13-0103-T. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.