Inhibitor of DNA-binding-1 (ID1) is a transcription factor that belongs to the helix-loop-helix family. High ID1 expression is associated with poor prognosis and high chemoresistance in cancer patients. USP1 is a deubiquitinating (DUB) enzyme that rescues ID1 from proteasome degradation. C527 is a small molecule inhibitor of USP1 with an IC50 value of 0.88 ± 0.03μM. It also inhibited the DUB activity of USP5, UCH-L3, and the USP12/USP46 complex with IC50 values of 1.65±0.42μM, 2.18±0.69μM, and 5.97±0.37μM, respectively. C527 promoted the degradation of ID1 in human U20S osteosarcoma cells in a dose-dependent manner. In Hela cells, treatment with C527 (10–50μM) for 8hr increased the levels of Ub-FANCD2 and Ub-FANCI. Pretreatment of Hela cells with 1μM C527 for 24hr enhanced the cytotoxicity of Mitomycin C and Camptothecin. C527 at 0.5–5μM dose-dependently inhibited DRGFP reporter for homologous recombination repair activity. Pre-incubation of Hela cell with 5μM C527 for 1hr inhibited Camptothecin-induced RAD51 foci formation in Hela cells.[1]
作用机制
C527 is a pan-deubiquitinating enzyme inhibitor that inhibits the catalytic activity of USP1 and other DUB enzymes.[1]
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