The ubiquitin-specific peptidases (USPs) are the main members of the deubiquitinase (DUB) family. USP1 by itself exhibits low DUB activity; however, this activity is significantly enhanced when bound as a USP1/UAF1 complex. SJB2-043 is an inhibitor of USP1/UAF1 with IC50 value of 0.544 μM. SJB2-043 inhibits the salvaging of DNA-binding-1 (ID1), FANC1 and FANCD2 proteins by Usp1 from proteosomal degradation and as a result caused an increase in cell death and sensitisation to DNA damaging agents. In vitro, SJB2-043 caused a dose-dependent decrease in the number of viable K562 cells, with an EC50 of approximately 1.07 μΜ. SJB2-043 induced apoptosis of chronic myelogenous leukemia (CML) K562 cells in a dose-dependent manner. In addition, low dose treatments with SJB2-043 activated differentiation of K562 cells into hemoglobin expressing erythroid cells. SJB2-043 exhibited dose-dependent cytotoxicity on the primary bone marrow as well as peripheral blood from AML patients. Moreover, SJB2-043 treatment caused inactivation of USP1 and promoted ID 1 degradation in primary AML cells[2].
搜索
