- 生物活性
LY364947是一种有效的，ATP竞争性的TGFβR-I抑制剂，IC50为59 nM，比作用于TGFβR-II选择性高7倍。
- 体外研究
LY364947 is an ATP competitive and tight-binding inhibitor, inhibiting phosphorylation of P-Smad3 by TGFβR-I kinase with Ki of 28 nM. LY364947 inhibits in vivo Smad2 phosphorylation within the NMuMg cells with IC50 of 135 nM. LY364947 reverses TGF-β-mediated growth inhibition in NMuMg cells with IC50 of 0.218 μM. LY364947 potentiates the xVent2-lux BMP4 response in NMuMg cells by 30% at concentrations as low as 0.25 μM. LY364947 (2 μM) prevents TGF-β-induced epithelial−mesenchymal transition in NMuMg cells. LY364947 (3 μM) induces expression of Prox1 and LYVE-1 in almost all HDLECs after 24 hours. LY364947 promotes nuclear export of Foxo3a, with low Smad2/3 and high Akt phosphorylation levels in leukaemia-initiating cells. LY364947 (< 20 μM) suppresses leukaemia-initiating cells colony-forming ability after co-culture with OP-9 stromal cells.
- 体内研究
LY364947 (1 mg/kg i.p.) accelerates lymphangiogenesis, as evidence by significantly increased the LYVE-1-positive areas, in a mouse model of chronic peritonitis. LY364947 (1 mg/kg i.p.) significantly increases the LYVE-1-positive areas in tumor tissues in tumor xenograft models using BxPC3 pancreatic adenocarcinoma cells. LY364947 (25 mg /kg) increases p-Akt and decreases nuclear Foxo3a in leukaemia-initiating cells in CML-affected mice.
- 生物活性
LY364947 (HTS 466284)是一种有效的ATP竞争性TGFβR-I抑制剂，无细胞试验中IC50为59 nM，比作用于TGFβR-II选择性高7倍。
- 靶点
Target
Value
TGFβRI
(Cell-free assay)
59 nM
RIPK2
(Cell-free assay)
0.11 μM
CK1δ
(Cell-free assay)
0.22 μM
TGFβRII
(Cell-free assay)
0.4 μM
MLK-7K
(Cell-free assay)
1.4 μM
- 体外研究
LY364947是一种ATP竞争性，紧密结合抑制剂，通过TGFβR-I激酶抑制P-Smad3磷酸化，Ki为28 nM。LY364947抑制体内Smad2磷酸化，NMuMg细胞中IC50 为135 nM。LY364947逆转NMuMg细胞中TGF-β介导的生长抑制，IC50为0.218 μM。LY364947在0.25 μM的低浓度下，使NMuMg细胞中的xVent2-lux BMP4响应增强30%。LY364947 (2 μM)防止NMuMg 细胞中TGF-β诱导的上皮间叶细胞转化。 LY364947 (3 μM)处理24小时后，几乎在所有HDLECs中诱导Prox1和 LYVE-1表达。 LY364947促进Foxo3a的核输出，在白血病阳性细胞中具有低Smad2/3和高Akt磷酸化水平。与OP-9基质细胞共培养后，LY364947 (< 20 μM)抑制白血病阳性细胞的集落形成能力。
- 体内研究
在慢性腹膜炎小鼠模型中，显著增加的LYVE-1-阳性区域表明，LY364947(1 mg/kg i.p.)加速淋巴管生成。BxPC3胰腺癌细胞的肿瘤异种移植模型中，LY364947 (1 mg/kg i.p.)显著增加肿瘤组织中LYVE-1-阳性区域。在感染CML的小鼠体内白血病阳性细胞中，LY364947 (25 mg /kg)增加p-Akt，并减少细胞核Foxo3a。
