USP1 inhibitor 38-P2 is a potent, selective, reversible, and noncompetitive ubiquitin-specific protease 1 (USP1) inhibitor with IC50 of 3.8 nM (USP1-UAF1).
38-P2 exhibits potent antiproliferative activity against NCI-H1299 cells with IC50 of 0.5 nM.
38-P2 strongly inhibits the proliferation of BRCA1-deficient MDA-MB-436 cells with an IC50 value of <0.03 nM, with no activity in normal cell lines HL-7702 and IM-9 (IC50s > 10 μM).
38-P2 selectively inhibits the cleavage of K63-linked diubiquitin by USP1-UAF1, while exhibiting negligible inhibition of other tested USPs, including USP4, USP7, USP8, USP9X, USP15, and USP25.
38-P2 induces S-phase arrest in BRCA1-deficient MDA-MB-436 cells and G2/M phase arrest in MDA-MB-436/OP cells, enhances the sensitivity of resistant cells to Olaparib.
38-P2 (75 mg/kg and 150 mg/kg daily, oral) significantly inhibited the growth of MDA-MB-436 xenografts on MDA-MB-436 xenografts in nude mice, demonstrated an increase in Ub-PCNA protein levels.