FLT3/D835Y-IN-1

FLT3/D835Y-IN-1 (compound 13a) is a orally active, potent and selective FLT3 and FLT3/D835Y inhibitor, with IC50 values of 0.26 nM and 0.18 nM, respectively. FLT3/D835Y-IN-1 also blocks tumor growth, has anticancer efficacy, and can be used to research for AML (acute myeloid leukemia)[1].

Research Areas >> Cancer

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

FLT3/D835Y:0.18 nM (IC50)

FLT3/D835Y-IN-1 (compound 13a) (100 nM, 3 h) potently inhibits Ba/F3-FLT3-ITD, Ba/F3-FLT3-ITD/D835Y, Ba/F3-FLT3-ITD-F691L cell lines, and AML cells proliferation[1]. FLT3/D835Y-IN-1 (3-30 nM, 16 h) significantly inhibit FLT3, AKT, ERK, and STAT5 pathways[1]. Cell Proliferation Assay Cell Line: Ba/F3-FLT3-ITD, Ba/F3-FLT3-ITD/D835Y, and Ba/F3-FLT3-ITD-F691L cell lines, AML cells[1] Concentration: 100 nM Incubation Time: 3 h Result: Inhibited Ba/F3-FLT3-ITD, Ba/F3-FLT3-ITD/D835Y, Ba/F3-FLT3-ITD-F691L, MV4-11, MOLM14, and MOLM14-ITD/D835Y proliferation, with GI50 values of 0.59, 0.73, 5.54, 1.30, 6.20, and 4.58 nM, respectively. Western Blot Analysis Cell Line: MOLM14-ITD/D835Y and MOLM14-ITD/F691L cells[1]. Concentration: 3, 10, and 30 nM Incubation Time: 16 h Result: Significantly inhibited the FLT3, AKT, ERK, and STAT5 pathways at lower dosages.

FLT3/D835Y-IN-1 (10 mg/kg, IP, daily, 6 days per week) significantly suppresses tumor growth and exhibits potent antitumor activity against MOLM14-ITD/D835Y cells[1]. FLT3/D835Y-IN-1 (10 mg/kg, IV or Orally, single) displays extremely low AUC and high clearance[1]. Pharmacokinetic Parameters of FLT3/D835Y-IN-1 in ICR mice[1]. Parameters 13a AUClast (ng*h/mL) 1360 ± 110 CL (L/h/kg) 6.96 ± 0.66 Vss (L/kg) 14.8 ± 0.7 T1/2 (h) 1.5 ± 0.1 Animal Model: NOD/SCID mice (6 weeks, male, nine mice per group)[1] Dosage: 10 mg/kg Administration: IP, daily, 6 days per week, from day 7 to day 29 Result: Significantly suppressed tumor growth. Animal Model: ICR mice (7–8 weeks, male)[1] Dosage: 10 mg/kg, dissolved in a solution (10% DMSO, 40% PEG400, and 50% PBS) Administration: IV or Orally, single (Pharmacokinetic Analysis) Result: Displayed extremely low AUC and high clearance.

[1]. Lee JH, Shin JE, Kim W, et al. Discovery of indirubin-3'-aminooxy-acetamide derivatives as potent and selective FLT3/D835Y mutant kinase inhibitors for acute myeloid leukemia. Eur J Med Chem. 2022 Apr 21;237:114356.