Cathepsin D inhibitor N-8 is a potent, specific inhibitor of Cathepsin D (CTSD) with 1SPR KD of 0.58 uM, effectively inhibits proliferation and induces apoptosis in leukemia cells with high CTSD expression.
N-8 demonstrates potent inhibitory activity in U937 cells with IC50 of 5.895 uM.
N-8 effectively inhibits proliferation of MV4-11 and MOLM-13 cells with IC50 values (IC5==5.9-11.4 uM) in the micromolar range and exerted similar effects in venetoclax-resistant AML cells (MOLM-13-VEN-R and MV4-11-VEN-R).
N-8 induces apoptosis in both AML cells and venetoclax-resistant AML cells in a dose-dependent manner, also showed significant pro-apoptotic activity in primary AML cells.
N-8 inhibits AML by promoting TRIM21-mediated degradation of the anti-apoptotic proteins BCL2, BCL-XL, and MCL1.
N-8 (30 mg/kg, PO, QD) attenuates the progression of AML in mice xenografted with U937 AML cells (AML mice), reduces BCL2, BCL-XL, and MCL1 expression in spleen and BM cells.