Eleven-Nineteen-Leukemia Protein IN-3, an orally active ENL YEATS domain inhibitor, exhibits potent activity with an IC50 of 15.4 nM. It downregulates MYC expression via ENL in cells and enhances ENL protein's thermal stability in vitro [1].

Eleven-Nineteen-Leukemia YEATS domain:15.4 nM

Eleven-Nineteen-Leukemia Protein IN-3 (Compound 28) exhibits significant inhibitory effects on MV4-11 and MOLM-13 cell lines with IC50 values of 4.8 µM and 8.3 µM, respectively [1]. At 5 µM for 6 hours, it increases the thermal stability of the endogenous ENL protein without impacting GAS41 protein stability. Additionally, it inhibits MOLM-13 cell growth [1], suppressing MYC oncogene expression by approximately 50% at 5 µM over 72 hours. When combined with JQ-1, it further downregulates MYC expression in ENL target genes [1].

Eleven-Nineteen-Leukemia Protein IN-3 (Compound 28) demonstrated oral bioavailability at a dose of 30 mg/kg when administered orally as a single dose [1]. When given intravenously at 5 mg/kg as a single injection, the compound showed higher systemic exposure [1]. Pharmacokinetic (PK) studies in male BALB/c mice revealed that for oral administration, the half-life (t 1/2) was 5.2 hours, with a time to peak concentration (T max) of 0.5 hours, a maximum concentration (C max) of 71.8 ng/mL, an area under the curve to the last measurable concentration (AUC 0-t) of 257 h•ng/mL, an extrapolated AUC (AUC 0-∞) of 272 h•ng/mL, and a mean residence time (MRT 0-∞) of 5.5 hours. For intravenous administration, the t 1/2 was 4.0 hours, AUC 0-t was 8290 h•ng/mL, AUC 0-∞ was 8690 h•ng/mL, volume of distribution at steady state (V ss) was 0.8 L/kg, clearance (CL) was 9.6 mL/min/kg, MRT 0-∞ was 1.3 hours, and bioavailability (F %) was 0.5%.