N-(1,1-二甲基乙基)-3-[[5-甲基-2-[[4-(4-甲基-1-哌嗪基)苯基]氨基]-4-嘧啶基]氨基]苯磺酰胺

TG101209是一种选择性的JAK2抑制剂，IC50为6 nM，对Flt3和RET作用效果稍弱，IC50分别为25 nM和17 nM，作用于JAK2比作用于JAK3选择性高30倍左右，对JAK2V617F和MPLW515L/K突变型敏感。 TG101209 is an orally bioavailable, small molecule, ATP-competitive inhibitor towards several tyrosine kinases. TG101209 inhibits growth of Ba/F3 cells expressing JAK2V617F or MPLW515L mutations with an IC50 of B200 nM. In a human JAK2V617F-expressing acute myeloid leukemia cell line, TG101209 inducs cell cycle arrest and apoptosis, and inhibits phosphorylation of JAK2V617F, STAT5 and STAT3. TG101209 suppresses growth of hematopoietic colonies from primary progenitor cells harboring JAK2V617F or MPL515 mutations. TG101209 significantly reduces STAT5 phosphorylation without affecting the total amount of STAT5 protein. TG101209 inhibits survivin and reduces phosphorylation of STAT3 in HCC2429 and H460 lung cancer cells. TG101209 results in radio sensitization of HCC2429 and H460 lung cancer cells in vitro. A recent study indicates TG101209 abrogates BCR-JAK2 and STAT5 phosphorylation, decreases Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. 100 mg/kg of TG101209 effectively prolongs the survival in JAK2V617F-induced disease (10 days). Compared with placebo-treated animals, TG101209-treated animals exhibit statistically significant, dose-dependent reduction in the circulating tumor cell burden at day +11 to 20%. TG101209是一种选择性的JAK2抑制剂，无细胞试验中IC50为6 nM，对Flt3和RET (c-RET)作用效果稍弱，IC50分别为25 nM和17 nM，作用于JAK2比作用于JAK3选择性高30倍左右，对JAK2V617F和MPLW515L/K突变型敏感。

Target	Value
JAK2 (Cell-free assay)	6 nM
RET (Cell-free assay)	17 nM
FLT3 (Cell-free assay)	25 nM
JAK3 (Cell-free assay)	169 nM

TG101209是一种口服生物可利用的，小分子，ATP竞争性的几种酪氨酸激酶抑制剂。TG101209抑制表达JAK2V617F或MPLW515L突变体的Ba/F3细胞生长，IC50为B200 nM。在表达人JAK2V617F的急性髓细胞性白血病细胞系中，TG101209诱导细胞周期阻滞和细胞凋亡，并抑制JAK2V617F，STAT5和STAT3磷酸化作用。TG101209抑制来自负荷JAK2V617F或MPL515突变体的原代祖细胞中造血细胞集落的生长。 TG101209显著减少STAT5磷酸化，而不影响STAT5蛋白质的总量。 在体外HCC2429和H460肺癌细胞中，TG101209抑制存活素，并降低STAT3的磷酸化作用。TG101209导致体外HCC2429和H460肺癌细胞放射致敏。一项最近的研究表明TG101209废除BCR-JAK2和STAT5磷酸化，减少Bcl-xL表达，并引起转化的Ba/F3细胞凋亡。

100 mg/kg TG101209有效延长JAK2V617F诱发的患病(10天)动物的存活时间。与安慰剂处理的动物相比，TG101209处理的动物体内循环肿瘤细胞负荷表现出统计学显著的，剂量依赖性减少，在+11天时减少比例达到20%。