LSD1-IN-48

LSD1-IN-48 is a cyclopropylamine-pyrimidine derivative and a highly selective LSD1 inhibitor with an IC50 of 7.87 nM against human targets. It elevates H3K4me1/2 histone methylation levels and induces apoptosis, upregulates CD86, downregulates SOX2 and CD44, and inhibits cancer cell proliferation. LSD1-IN-48 is applicable for research in acute myeloid leukemia.

LSD1:7.87 nM

LSD1-IN-48 (7a) is a potent inhibitor of recombinant LSD1 with an IC50 of 7.87 nM, demonstrating selectivity over MAO-A and MAO-B by factors of 127 and 1270, respectively. It inhibits the proliferation of acute myeloid leukemia cells MV-4-11, HL-60, and THP-1 with IC50 values of 0.36 μM, 0.48 μM, and 1.12 μM, respectively. At concentrations of 10-100 μM, LSD1-IN-48 binds directly to LSD1 extracted from MV-4-11 cells, protecting it from alkaline protease hydrolysis in a dose-dependent manner. It exhibits in vitro metabolic stability in human liver microsomes with a half-life of 7.26 minutes and an intrinsic clearance rate of 172 mL/min/kg. Additionally, LSD1-IN-48 (0.5-2 μM; 2 days) increases histone methylation levels of H3K4me1 and H3K4me2 in MV-4-11 cells in a dose-dependent manner and induces apoptosis, raising the total apoptosis rate to 33.19% at 2 μM concentration through the activation of caspase-mediated pathways. Over 4 days, the compound also upregulates the differentiation marker CD86 in a dose-dependent way, increasing its expression by 19.18% at 2 μM concentration. Finally, at 0.5-2 μM for 96 hours, it dose-dependently reduces the levels of stem cell-related proteins SOX2 and CD44 in MV-4-11 cells, thereby diminishing cancer stem cell characteristics.