JAK3 Inhibitor VI

JI6 is a potent, selective and orally active FLT3 inhibitor, with IC50s of ∼40, 8, and 4 nM for FLT3-WT, FLT3-D835Y, and FLT3-D835H, respectively. JI6 also inhibits JAK3 and c-Kit, with IC50s of ∼250 and ∼500 nM, respectively. JI6 can be used for the research of acute myeloid leukemia[1].

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> JAK

Signaling Pathways >> Epigenetics >> JAK

Signaling Pathways >> Stem Cell/Wnt >> JAK

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

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Kit

FLT3-D835H:4 nM (IC50)

FLT3-D835Y:8 nM (IC50)

FLT3-WT:40 nM (IC50)

JAK3:~250 nM (IC50)

c-Kit:~500 nM (IC50)

JI6 (3-1000 nM; 1-4 days) 以剂量依赖性方式抑制 MV4-11 细胞的活力，IC50 值为 ∼25 nM[1]。 JI6 (1-2000 nM; 48 h) 有效抑制表达 FLT3-ITD，FLT3-D835Y 和 FLT3-D835H 的 HCD-57 细胞的活力，IC50 值为 ∼40 nM，对亲代 HCD-57 或表达 JAK2V617F 的细胞基本没有影响[1]。 JI6 (100-500 nM; 24 h) 在表达 FLT3-ITD 和 FLT3-D835Y 的 HCD-57 细胞中诱导细胞凋亡和细胞周期停滞[1]。 JI6 (50-500 nM; 3 h) 抑制表达 FLT3-ITD 和 FLT3-D835Y 的 HCD-57 细胞中 FLT3 及 ERK 和 Akt 的磷酸化[1]。 Cell Viability Assay[1] Cell Line: MV4-11, HL60, Karpas 299, and Jurkat cells Concentration: 3-1000 nM Incubation Time: 48 hours Result: Inhibited MV4-11 cells and no effects of JI6 on the three remaining cells at a concentration as high as 1 μM. Apoptosis Analysis[1] Cell Line: FLT3-ITD- and FLT3-D835Y-transformed HCD-57 cells Concentration: 100, 500 nM Incubation Time: 24 hours Result: Increased the percentage of apoptotic and necrotic cells and displayed no effects on the apoptosis of the parent HCD-57 cells. Cell Cycle Analysis[1] Cell Line: FLT3-ITD- and FLT3-D835Y-transformed HCD-57 cells Concentration: 100, 500 nM Incubation Time: 24 hours Result: Significantly reduced G2 and S phase cells and increased G1 phase cells in both FLT3-ITD and D835Y cells. Cell Viability Assay[1] Cell Line: FLT3-ITD- and FLT3-D835Y-transformed HCD-57 cells Concentration: 50, 100, 500 nM Incubation Time: 3 hours Result: Inhibited phosphorylation of FLT3, ERK1, ERK2 and Akt.

JI6 (15 mg/kg; i.p. daily for 3 weeks) 抑制免疫缺陷小鼠体内表达 FLT3-D835Y 的 HCD-57 增殖并延长小鼠存活期[1]。 JI6 (25 mg/kg; p.o. daily for 3 weeks) 抑制 FLT3-ITD 敲入小鼠的骨髓增生表型[1]。 JI6 (100 mg/kg; a single i.p.) 在表达 FLT3-D835Y 的小鼠中显着抑制 FLT3 磷酸化和下游信号转导[1]。 Animal Model: NSG mice (10-12 weeks old, male) were implanted with FLT3-D835Y-transformed HCD-57 cells[1] Dosage: 15 mg/kg Administration: I.p. daily for 3 weeks Result: Reduced the spleen size and prolonged the survival of these mice.

[1]. Chen Y, et, al. Identification of an orally available compound with potent and broad FLT3 inhibition activity. Oncogene. 2016 Jun 9;35(23):2971-8.