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]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  22RV1	-	Growth Inhibition Assay	-	IC50=5.80019 μM	SANGER
  5637	-	Growth Inhibition Assay	-	IC50=13.7759 μM	SANGER
  639-V	-	Growth Inhibition Assay	-	IC50=27.0245 μM	SANGER

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• 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.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01672736	Multiple Myeloma	Phase 1 Phase 2	Terminated(The Sponsor decided... more >> to stop further manufacture the study drug 'Linsitinib' in Nov 2015.) Collapse <<	-	United States, Georgia ... more >> Emory University Winship Cancer Institute Atlanta, Georgia, United States, 30322 United States, Illinois University Of Chicago Medical Center Chicago, Illinois, United States, 60637 Canada, Nova Scotia Queen Elizabeth II Health Sciences Center Halifax, Nova Scotia, Canada, B3H2Y9 Canada, Ontario University Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Canada, Quebec Hôpital Maisonneuve-Rosemont Montreal, Quebec, Canada, H1T 2M4 Sir Mortimer B. Davis-Jewish General Hospital Montreal, Quebec, Canada, H3T 1E3 Collapse <<
  NCT01465815	Recurrent Skin Cancer ... more >> Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity Squamous Cell Carcinoma of the Skin Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity Collapse <<	Phase 1 Phase 2	Withdrawn(Drug manufacturer, A... more >>stellas Pharma, informed us that safety and efficacy of Erlotinib and OSI-906 in other oncology studies was determined to be unfavorable.) Collapse <<	-	United States, Oregon ... more >> OHSU Knight Cancer Institute Portland, Oregon, United States, 97239 Collapse <<
  NCT01013506	Breast Cancer	Phase 2	Withdrawn(Study was abandoned ... more >>before opening to accrual. Replaced by another study.) Collapse <<	-	-

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