FLT3/HDAC-IN-3

FLT3/HDAC-IN-3 is a dual inhibitor targeting both FLT3 and HDAC. It shows potent inhibition of FLT3 (IC50 = 14 nM), HDAC1 (IC50 = 27 nM), HDAC6 (IC50 = 20 nM), and FLT3D853Y (IC50 = 55 nM), while exhibiting weak activity against HDAC8 and no activity against HDAC4. The compound is characterized by kinase selectivity, plasma stability, and stability in human liver microsomes. It demonstrates antiproliferative effects in various hematologic malignancy cell lines. In the Jeko-1 xenograft model, FLT3/HDAC-IN-3 exhibits inhibitory effects with no significant toxicity observed, making it useful for research in hematologic malignancies.

FLT3:14 nM

FLT3/HDAC-IN-3 (compound 6s) effectively inhibits the proliferation of MV-4-11 cells (IC 50 = 29 nM) and Jeko-1 cells (IC 50 = 99 nM) over 72 hours, demonstrating selective cytotoxicity with an IC 50 of 80 μM in HaCaT cells. It inhibits the phosphorylation of FLT3 and STAT5 and increases H3Ac levels in a dose-dependent manner, also upregulating Bax in MV-4-11 cells when exposed to concentrations ranging from 0-1000 nM for 72 h. In both MV-4-11 and Jeko-1 cells, it induces dose-dependent cell death, ROS accumulation, and reduces mitochondrial membrane potential. Additionally, FLT3/HDAC-IN-3 promotes time- and dose-dependent apoptosis over 48 to 72 hours, and arrests the cell cycle at the G2 phase in MV-4-11 cells in a concentration-dependent manner. In rat plasma, the compound shows good stability with a retention rate of 67.8% after 72 hours at 200 μM. It also exhibits favorable metabolic stability in human liver microsomes with a half-life of 165 minutes and intrinsic clearance of 7.56 mL/min/kg.

FLT3/HDAC-IN-3 (compound 6s) (15-30 mg/kg; intraperitoneal injection; once daily; for 15 days) effectively and dose-dependently inhibits mantle cell lymphoma growth in Jeko-1 xenograft mice, achieving a tumor growth inhibition rate (TGI) of 53.34% at a dose of 30 mg/kg, with no observed toxicity.