761437-28-9
中文名稱
TAE226 (NVP-TAE226)
英文名稱
TAE226 (NVP-TAE226)
CAS
761437-28-9
分子式
C23H25ClN6O3
分子量
468.936
MOL 文件
761437-28-9.mol
更新日期
2024/11/08 11:24:21
761437-28-9 結(jié)構(gòu)式
基本信息
中文別名
化合物TAE226雙重酪氨酸激酶抑制劑(NVP-TAE 226)
2-[[5-氯-2-[[2-甲氧基-4-(4-嗎啉)苯基]氨基]-4-嘧啶]氨基]-N-甲基苯甲酰胺
2-[[5-氯-2-[[2-甲氧基-4-(4-嗎啉基)苯基]氨基]-4-嘧啶基]氨基]-N-甲基苯甲酰胺
英文別名
TAE226CS-1694
NVP-TAE 226
TAE-226, >98%
TAE226 (NVP-TAE226)
TAE226 (NVP-TAE226), >98%
TAE226 (NVP-TAE226) USP/EP/BP
TAE226
TAE-226
TAE 226
NVPTAE226
2-((5-Chloro-2-((2-methoxy-4-morpholinophenyl)-amino)pyrimidin-4-yl)amino)-N-methylbenzamide
2-[[5-Chloro-2-[[2-methoxy-4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]amino]-N-methylbenzamide
所屬類別
生物化工：FAK 抑制劑物理化學(xué)性質(zhì)
密度1.349
儲(chǔ)存條件-20°C儲(chǔ)存
溶解度≥23.45 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH
酸度系數(shù)(pKa)14.57±0.46(Predicted)
形態(tài)固體
顏色White to khaki
常見(jiàn)問(wèn)題列表
生物活性
TAE226 (NVP-TAE226)是一種有效的FAK抑制劑，IC50為5.5 nM，最有效作用于Pyk2，對(duì)InsR， IGF-1R， ALK和c-Met作用效果比其弱10到100倍左右。體外研究
NVP-TAE226 (< 1 μM) inhibits extracellular matrix-induced autophosphorylation of FAK (Tyr397) in serum-starved U87 cells. NVP-TAE226 (< 1 μM) also inhibits IGF-I-induced phosphorylation of IGF-1R and activity of its downstream target genes such as MAPK and Akt in both U87 and U251 cells. NVP-TAE226 (<10 μM) retards tumor cell growth and attenuats G(2)-M cell cycle progression associated with a decrease in cyclin B1 and phosphorylated cdc2 (Tyr15) protein expression in both U87 and U251 cells. NVP-TAE226 (1 μM) inhibits tumor cell invasion by at least 50% compared with the control in an in vitro Matrigel invasion assay in glioma cell lines. NVP-TAE226 (1 μM) treatment of glioma cell lines containing wild-type p53 mainly exhibits G(2)-M arrest, whereas glioma cell lines bearing mutant p53 undergoes apoptosis, as evidence by detection of caspase-3/7 activation and poly(ADP-ribose) polymerase cleavage and by an Annexin V apoptosis assay. NVP-TAE226 (5 μM) inhibits phosphorylation of FAK in the human neuroblastoma cell line SK-N-AS. NVP-TAE226 (<10 μM) treatment of the human neuroblastoma cell line SK-N-AS leads to decrease in cellular viability, cell cycle arrest, and an increase in apoptosis. NVP-TAE226 (0.1 μM-10 μM) inhibits tube formation of HMEC1 cells.體內(nèi)研究
NVP-TAE226 (75 mg/kg) significantly increases the survival rate of mice bearing intracranial glioma xenografts. NVP-TAE226 (100 mg/kg, oral) exerts significant decrease in microvessel density in a human colon cancer model in SCID mice. NVP-TAE226 (100 mg/kg, oral) efficiently inhibits MIA PaCa-2 human pancreatic tumor growth without body weight loss in vivo model. NVP-TAE226 inhibits 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner in vivo model, associated with inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473.生物活性
TAE226 (NVP-TAE226) 是一種有效的FAK抑制劑，IC50為5.5 nM，最有效作用于Pyk2，對(duì)InsR， IGF-1R， ALK和c-Met作用效果比其弱10到100倍左右。TAE226 (NVP-TAE226) 可誘導(dǎo)凋亡。靶點(diǎn)
| Target | Value |
|
PYK2
(cell-free assay) | 3.5 nM |
|
FAK
(cell-free assay) | 5.5 nM |
|
Insulin Receptor
(cell-free assay) | 43.5 nM |
|
IGF-1R
(cell-free assay) | 140 nM |
|
c-Met
(cell-free assay) | 160 nM |
體外研究
在血清饑餓的U87細(xì)胞中，NVP-TAE226(< 1 μM)抑制細(xì)胞外基質(zhì)誘導(dǎo)的FAK(Tyr397)自身磷酸化。U87和U251細(xì)胞中，NVP-TAE226 (< 1 μM)也會(huì)抑制IGF-I-誘導(dǎo)的IGF-1R磷酸化和其下游靶點(diǎn)基因，比如MAPK 和Akt的活性。U87和U251細(xì)胞中，NVP-TAE226 (<10 μM)阻礙腫瘤細(xì)胞生長(zhǎng)，并減弱G(2)-M細(xì)胞周期進(jìn)程，其與細(xì)胞周期素B1和磷酸化cdc2 (Tyr15)蛋白質(zhì)表達(dá)的減少相關(guān)。在體外膠質(zhì)瘤細(xì)胞系人工基底膜侵襲實(shí)驗(yàn)中，與對(duì)照組相比，NVP-TAE226 (1 μM)抑制至少50%的腫瘤細(xì)胞侵襲。根據(jù)caspase-3/7活化和poly(ADP-ribose)聚合酶裂解以及膜聯(lián)蛋白V凋亡試驗(yàn)，NVP-TAE226 (1 μM)治療對(duì)膠質(zhì)瘤細(xì)胞系，包括野生型p53，僅表現(xiàn)出G(2)-M期阻滯，而負(fù)荷突變體p53的膠質(zhì)瘤細(xì)胞會(huì)發(fā)生細(xì)胞凋亡。在人成神經(jīng)細(xì)胞瘤細(xì)胞系SK-N-AS中，NVP-TAE226 (5 μM)抑制FAK磷酸化。NVP-TAE226 (<10 μM)對(duì)人成神經(jīng)細(xì)胞瘤細(xì)胞系SK-N-AS的治療導(dǎo)致細(xì)胞活性降低，細(xì)胞周期阻滯，以及細(xì)胞凋亡增加。 NVP-TAE226 (0.1 μM-10 μM)抑制HMEC1細(xì)胞的微管形成。
體內(nèi)研究
NVP-TAE226(75 mg/kg)顯著增加負(fù)荷顱內(nèi)膠質(zhì)瘤異種移植物的小鼠的存活率。在人結(jié)腸癌SCID 小鼠模型中，NVP-TAE226 (100 mg/kg，口服)顯著降低微血管密度。在體內(nèi)模型中，NVP-TAE226 (100 mg/kg，口服)有效抑制MIA PaCa-2人胰腺腫瘤生長(zhǎng)，而不引起體重?fù)p失。 在體內(nèi)模型中，NVP-TAE226劑量依賴性抑制4T1小鼠乳腺瘤生長(zhǎng)和肺轉(zhuǎn)移，與Y397上FAK的自身磷酸化和絲氨酸473上Akt磷酸化的抑制相關(guān)。