FLT3-IN-15

FLT3-IN-15 is a highly potent and orally active FLT3 inhibitor with IC50s of 0.87 nM and 0.32 nM for FLT3 and FLT3/D835Y, respectively. FLT3-IN-15 can be used for researching acute myeloid leukemia[1].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> FLT3

IC50: 0.87 nM (FLT3), 0.32 nM (FLT3/D835Y)[1]

FLT3-IN-15 (compound 36) (0-100 nM) exhibits anti-proliferative activities against MOLM14 cell lines[1]. FLT3-IN-15 (0-1 μM; 72 hours) shows extremely more sensitive against MV4-11 cells than K562 cell line, and displayed good safety profiles against other cancer cell lines[1]. FLT3-IN-15 (0.01-1 μM; 4 hours) shows strongly blockage of the phosphorylation of STAT5 and Erk1/2 in MV4-11 cells[1]. Cell Proliferation Assay Cell Line: MOLM14 wild type cells, MOLM14-ITD cells, MOLM14-ITD-D835Y cells, MOLM14-ITD-F691L cells[1] Concentration: 0-100 nM Incubation Time: Result: Exhibited anti-proliferative activities against MOLM14 cell lines, with GI50s of 4.88 ± 0.67 nM, 1.85 ± 0.06 nM, 1.87 ± 0.36 nM and 3.27 ± 0.99 nM in MOLM14 wild type cells, MOLM14-ITD cells, MOLM14-ITD-D835Y cells and MOLM14-ITD-F691L cells, respectively. Cell Proliferation Assay Cell Line: MV4-11, K562, A549, HepG2, MDA-MB-231, HCT-116, PC3 and SK-OV-3[1] Concentration: 0-1 μM Incubation Time: 72 hours Result: Showed extremely more sensitive against MV4-11 cells (GI50 = 1 nM) than K562 cell line, and displayed good safety profiles against other cancer cell lines. Western Blot Analysis Cell Line: MV4-11[1] Concentration: 10 nM, 100 nM and 1 μM Incubation Time: 4 hours Result: Showed strongly blockage of the phosphorylation of STAT5 and Erk1/2.

FLT3-IN-15 (20 mg/kg; PO; daily, for 21 days) results in the rapid and complete remission of tumors in all mice[1]. FLT3-IN-15 (2000 mg/kg; PO; single) causes one female mouse died at day 6, and the LD50 value is calculated as 4,950 mg/kg in female mice[1]. FLT3-IN-15 (10 μM) shows 21.4% inhibition of hERG ligand binding[1]. FLT3-IN-15 (10 mg/kg; PO and IV; single) exhibits an AUClast of 25.0 μg·min/mL, a Cmax of 36.5 ng/mL, and a remarkable increase in the oral bioavailability of 42.6%[1]. Pharmacokinetic Parameters of FLT3-IN-15 in male ICR mice[1]. PO (10 mg/kg) IV (10 mg/kg) AUClast (μg·min/mL) 25.0 ± 11.6 58.5 ± 57.4 AUCinf (μg·min/mL) 62.1 ± 58.6 103.4 ± 95.3 MRT (hr) 2811.3 ± 2713.0 1257.1 ± 1084.1 T1/2 (hr) 1775.7 ± 1901.0 1099.2 ± 945.8 CL (mL/min/kg) 158.7 ± 98.7 VSS (L/kg) 127891 ± 104764 Cmax (ng/mL) 36.5 ± 24.3 Tmax (min) 390.0 ± 366.0 Xu, 24h (%) 0.001 ± 0.0 0.002 ± 0.002 GI24h (%) 0.05 ± 0.05 0.24 ± 0.02 F (%) 42.9 Animal Model: BALB/c nu/nu (injected with MV4-11)[1] Dosage: 20 mg/kg Administration: PO; daily, for 21 days Result: Resulted in the rapid and complete remission of tumors in all mice, and no weight loss or any other signs of toxicity during the administration period. Animal Model: Female ICR mice[1] Dosage: 2000 mg/kg Administration: PO; single Result: Caused one female mouse of the 2,000 mg/kg group died at day 6 and the approximate lethal dose (ALD) is determined over 2,000 mg/kg in male mice and 2,000 mg/kg in female mice, respectively; the LD50 value was calculated as 4,950 mg/kg in female mice. Animal Model: Male ICR mice[1] Dosage: 10 mg/kg Administration: PO and IV; single (Pharmacokinetics Analysis) Result: Exhibited an AUClast of 25.0 μg·min/mL, a Cmax of 36.5 ng/mL, and a remarkable increase in the oral bioavailability of 42.6%.

[1]. Jeong P, Moon Y, Lee JH, et al. Discovery of orally active indirubin-3'-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia. Eur J Med Chem. 2020;195:112205.