生物活性

• 靶点

  IGF-1R IC50:35nM

  Insulin Receptor IC50:75nM

• 描述IGF-1R (insulin-like growth factor-1 receptor) plays a key role in transformation, growth and survival of malignant cells, and has been considered as a general and promising target for cancer treatment. Linsitinib is a potent and selective IGF-1R receptor with IC50 value of 35nM, also show inhibitory effect against Insulin receptor and insulin receptor-related receptor with IC50 values of 75nM for both (measured by purified recombinant kinase activity). Treatment with Linsitinib at concentration ranging in 0.01-1μM for 2h could dose-dependently inhibited autophosphorylation of IGF-1R, at phosphorylation of the downstream, including AKT, ERK and p70S6K with IC50 of 24nM, 130nM, 28nM and 60nM, respectively, in 3T3/huIGF-1R (LISN) cells. Also the inhibition on phosphorylation of both IGF-1R and IR by Linsitinib was shown in HT-29 and Colo-205 cells. The antiproliferative effect of Linsitinib could be observed in a panel of cell lines from various tumor types with IC50 ranging in 0.021-0.81μM, including HT29, Colo205, SW620 (colorectal), DU4475, MCF7 (breast), 3T3/huIGF-1R (mouse fibroblast), H358, H292 (non-small-cell lung), BxPC3 (pancreatic) and A673 (rhabdomyosarcoma) cell lines. A further study showed that a panel of non-small-cell lung cancer and colorectal cancer (CRC) tumor cell lines exhibiting an epithelial phenotype exhibited greater sensitivity to Linsitinib than those tumor cells that have undergone an epithelial–mesenchymal transition. A single oral dose of 75mg/kg Linsitinib inhibited the autophosphorylation of IGF-1R 2-24h after dose in LISN tumor xenograft models, suggesting the pharmacodynamics of this compound. Oral administration of Linsitinib at 75mg/kg once-daily for 12 days significantly inhibit tumor growth in a LISN xenograft model^[1].
• 作用机制Linsitinib can attach to the ATP-binding pocket of tyrosine kinase receptors, causing dual inhibition of both IR and IGF-1R.^[1]

• 动物研究
  剂量	Mice: 25 mg/kg[2] (p.o.), 5 mg/kg[1] (i.v.), 100 mg/kg[1] (p.o.) Rat: 5 mg/kg[1] (i.v.), 20 mg/kg[1] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Dose 5 mg/kg (i.v.) 25 mg/kg (p.o.) 5 mg/kg (i.v.) 100 mg/kg (p.o.) 2.5 mg/kg (i.v.) 5 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 100% (p.o.) 92% (p.o.) 64% (p.o.) AUC0→last 26741 ng·h/ml (p.o.) 424076 ng·h/ml (p.o.) 1328 ng·h/ml (p.o.) Tβ 2.64 h (i.v.) t1/2β 1.18 h (i.v.) T1/2β 2.14 h (i.v.) CL 12 ml/min/kg (i.v.) 4 ml/min/kg (i.v.) 39 ml/min/kg (i.v.) Cmax 16.04 μM (p.o.) 34.64 μM (p.o.) 1.20 μM (p.o.) AUC0→∞ 6954 ng·h/ml (i.v.) 23123 ng·h/ml (i.v.) 1066 ng·h/ml (i.v.) Vss 2.05 L/kg (i.v.) 0.79 L/kg (i.v.) 4.30 L/kg (i.v.)