Background:

SJB2-043 is a novel and potent inhibitor of USP1 with IC50 value of 0.544 μM [1].

Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme (DUB) and is a member of the ubiquitin-specific processing (UBP) family of proteases. It deubiquitinates a protein in the DNA repair pathway of the Fanconi anemia (FA) [1].

In the K562 cell line, SJB2-043 decreased USP1 levels in a dose-dependent way and caused degradation of the ID1 protein, which resulted from proteasomal degradation. Also, SJB2-043 decreased the levels of ID2 and ID3 proteins. Importantly, knockdown of USP1 inhibited cell growth and increased apoptosis. In primary AML cells, SJB2-043 inactivated USP1 and promoted ID 1 degradation. In primary human cord blood CD34+ cells, SJB2-043 in low micromolar levels inhibited cell growth. In HeLa cells, SJB2-043 increased the levels of Ub-FANCD2 and Ub-PCNA. And deubiquitination of FANCD2 is an important step in the BRCA/Fanconi anemia (FA) DNA repair pathway [1].

Reference:
[1].  Helena Mistry, Grace Hsieh, Sara S, et al. Buhrlage, et al. Small molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther, 2013, 12(12): 2651-2662.