GSK J4 HCl|1797983-09-5|安捷凯

Background

GSK-J4 HCl is a small-molecule inhibitor with highly efficient cell permeability and a pharmacologically selective inhibitor that preserves H3K27 methylation by inhibiting KDM6B. GSK-J4 HCl acts by interacting with α-ketoglutarate binding at the catalytic site of KDM6B. In addition, treatment with GSK-J4 HCl induced cell cycle arrest and cell death in different kinds of cancer cells with dismal toxicity to normal cells.

In vitro experiment indicated that GSK-J4 HCl could inhibit T. gondii at IC50 values of 2.37 μM. In addition, the TD50 value of GSK-J4 HCl against HFF was 34.6 μM. Based on these results, the calculated in vitro TI was 14.6 for GSK-J4 HCl. These data suggest that GSK-J4 HCl is a potent drug candidate against toxoplasmosis. In vivo study indicated that GSK J4 HCl could significantly elongate the survival time in acute murine toxoplasmosis model. Moreover, GSK-J4 HCl is a promising candidate for the treatment and prevention of toxoplasmosis.^[1]

参考文献:
[1].Liu S, et al. Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain. Parasit Vectors. 2020 May 11;13(1):242.

GSK-J4 HCl 是一种小分子抑制剂,具有高效的细胞渗透性和药理学选择性抑制剂,可通过抑制 KDM6B 来保持 H3K27 甲基化。 GSK-J4 HCl 通过与 KDM6B 催化位点的 α-酮戊二酸结合相互作用发挥作用。此外,GSK-J4 HCl处理可诱导不同类型癌细胞的细胞周期停滞和细胞死亡,对正常细胞具有不良毒性。

体外实验表明,GSK-J4 HCl 可以抑制弓形虫,IC50 值为 2.37 μM。此外,GSK-J4 HCl 对 HFF 的 TD50 值为 34.6 μM。基于这些结果,计算出的 GSK-J4 HCl 体外 TI 为 14.6。这些数据表明 GSK-J4 HCl 是一种有效的抗弓形虫病候选药物。体内研究表明,GSK J4 HCl 可显着延长急性小鼠弓形虫病模型的存活时间。此外,GSK-J4 HCl 有望成为治疗和预防弓形虫病的候选药物。^[1]

Protocol

Cell experiment [1]:

Cell lines

Human foreskin fibroblasts (HFFs, ATCC SCRC-1041) cells

Preparation Method

The T. gondii tachyzoites were maintained by repeat passage in monolayers of HFFs grown in DMEM supplemented with 10% (v/v) FBS and a cocktail of 1% (v/v) penicillin-streptomycin -glutamine at 37 °C and 5% CO₂ .

Reaction Conditions

GSK J4 HCl with initial concentration of 100 μM in the culture medium was added to the first column of HFFs (~?250 cells/well) in a 96-well half-area plate and then diluted serially across the plate by 2-fold dilutions, leaving the final column drug-free. Fifty tachyzoites were then added at a MOI of 1:5 to each well in six of the eight rows. After a 72h incubation, CPRG was added, and the absorbance was measured at 570 nm. Moreover, to measure the effect of each compound on the viability of host cells, CCK8 reagent was added to the two rows of uninfected HFFs and absorbance at 450 nm was measured after 2 h.

Applications

GSK-J4 HCl could inhibit T. gondii and show ability against toxoplasmosis.

Animal experiment [1]:

Animal models

Female BALB/c mice (6–8 weeks old, ~20 g)

Preparation Method

Mice were divided into 4 groups consisting of 15 mice each and injected intraperitoneally with 103 RH strains per animal. GSK J4 HCl were dissolved in DMSO and diluted in PBS prior to feeding to mice. After 4 h of infection, mice were orally administered with GSK J4 HCl for 5 consecutive days and were monitored for 30 days. Mice treated with pyrimethamine (50 mg/kg) were used as a positive control, and 1 ml PBS containing 11 μl of DMSO was used as a negative control.

Dosage form

50 mg/kg

Applications

GSK J4 HCl could significantly elongate the survival time in acute murine toxoplasmosis model. GSK-J4 HCl is a promising candidate for the treatment and prevention of toxoplasmosis.

参考文献:

[1]. Liu S, et al. Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain. Parasit Vectors. 2020 May 11;13(1):242.