TAE226 (NVP-TAE226)

TAE226 (NVP-TAE226)是一种有效的FAK抑制剂，IC50为5.5 nM，最有效作用于Pyk2，对InsR， IGF-1R， ALK和c-Met作用效果比其弱10到100倍左右。 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. 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. TAE226 (NVP-TAE226) 是一种有效的FAK抑制剂，IC50为5.5 nM，最有效作用于Pyk2，对InsR， IGF-1R， ALK和c-Met作用效果比其弱10到100倍左右。TAE226 (NVP-TAE226) 可诱导凋亡。

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

在血清饥饿的U87细胞中，NVP-TAE226(< 1 μM)抑制细胞外基质诱导的FAK(Tyr397)自身磷酸化。U87和U251细胞中，NVP-TAE226 (< 1 μM)也会抑制IGF-I-诱导的IGF-1R磷酸化和其下游靶点基因，比如MAPK 和Akt的活性。U87和U251细胞中，NVP-TAE226 (<10 μM)阻碍肿瘤细胞生长，并减弱G(2)-M细胞周期进程，其与细胞周期素B1和磷酸化cdc2 (Tyr15)蛋白质表达的减少相关。在体外胶质瘤细胞系人工基底膜侵袭实验中，与对照组相比，NVP-TAE226 (1 μM)抑制至少50%的肿瘤细胞侵袭。根据caspase-3/7活化和poly(ADP-ribose)聚合酶裂解以及膜联蛋白V凋亡试验，NVP-TAE226 (1 μM)治疗对胶质瘤细胞系，包括野生型p53，仅表现出G(2)-M期阻滞，而负荷突变体p53的胶质瘤细胞会发生细胞凋亡。在人成神经细胞瘤细胞系SK-N-AS中，NVP-TAE226 (5 μM)抑制FAK磷酸化。NVP-TAE226 (<10 μM)对人成神经细胞瘤细胞系SK-N-AS的治疗导致细胞活性降低，细胞周期阻滞，以及细胞凋亡增加。 NVP-TAE226 (0.1 μM-10 μM)抑制HMEC1细胞的微管形成。

NVP-TAE226(75 mg/kg)显著增加负荷颅内胶质瘤异种移植物的小鼠的存活率。在人结肠癌SCID 小鼠模型中，NVP-TAE226 (100 mg/kg，口服)显著降低微血管密度。在体内模型中，NVP-TAE226 (100 mg/kg，口服)有效抑制MIA PaCa-2人胰腺肿瘤生长，而不引起体重损失。 在体内模型中，NVP-TAE226剂量依赖性抑制4T1小鼠乳腺瘤生长和肺转移，与Y397上FAK的自身磷酸化和丝氨酸473上Akt磷酸化的抑制相关。