XL019 是一种具有口服活性的选择性JAK2抑制剂。它对JAK2的选择性是 100 多种丝氨酸/苏氨酸和酪氨酸激酶的 50 倍以上。它对 JAK2 V617F 和野生型 JAK2 细胞中 STAT3 和 STAT5 磷酸化有抑制作用。

XL019 is a potent and selective JAK2 inhibitor with IC50 of 2.2 nM, 100 fold selectivity over JAK1.

XL019具有优越的药效学特性,并且表现出良好的口服吸收性,在不同物种中表现适中的清除率和半衰期.在给药30,100和300 mg/kg XL019后,明显抑制下游标记pSTAT1和pSTAT3,导致pSTAT1的ED 50为42 mg/kg和pSTAT3的ED 50为210 mg/kg.XL019抑制小鼠HEL.92.1.7异种移植肿瘤生长,200 mg/kg和300 mg/kg XL019分别每天给药两次持续14天,表现60％和70％的抑制作用.

L019抑制JAK2以及突变形式JAK2V617F的激活,其可导致JAK-STAT信号传导途径的抑制并可诱导凋亡。与其他细胞系统相比,在EPO刺激红细胞系后,XL019显示出10倍以上的STAT5磷酸化选择性抑制（IC50 = 64 nM）。

FRET-Based Z′-Lyte Assay Detecting Peptide Substrate Phosphorylation: The kinases ABL1, ABL1(E255K), ABL1 (G250E), ABL1(T315I), and ABL1(Y253F) are P3049, PV3864, PV3865, PV3866, and PV3863 are full-length human recombinant protein expressed in insect cells and histidine-tagged. Inhibition activities of inhibitors against Abl1 and its mutants are performed in 384-well plates using the FRET-based Z′-Lyte assay system. Briefly, the kinase substrate is diluted into 5 μL of kinase reaction buffer; and the kinase is added. Compounds (10 nL) with indicated concentrations are then delivered to the reaction by using Echo liquid handler, and the mixture is incubated for 30 min at room temperature. Then 5 μL of 2X ATP solution is added to initiate the reaction, and the mixture is further incubated for 2 h at room temperature. The resulting reactions contains 10 μM (for wild-type Abl1, and mutants Y253F, Q252H, M351T, and H396P) or 5 μM (for mutants E255K, G250E, T315I) of ATP, 2 μM of Tyr2 Peptide substrate in 50 mM HEPES (PH 7.5), 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA, 0.0247 μg/mL Abl1, and inhibitors as appropriate. Then, 5 μL of development reagent is added, and the mixture is incubated for 2 h at room temperature before 5 μL of stop solution is added. Fluorescence signal ratio of 445 nm (Coumarin)/520 nm (fluorescin) is examined on an EnVision Multilabel Reader. The data are analyzed using Graphpad Prism5. The data are the mean value of three experiments.

945755-56-6

C25H28N6O2

444.539

DMSO:13 mg/mL (29.2 mM)
Ethanol:<1 mgml
Powder: -20°C for 3 years
In solvent: -80°C for 2 years