Linsitinib
(Synonyms: 顺式-3-[8-氨基-1-(2-苯基-7-喹啉基)咪唑并[1,5-A]吡嗪-3-基]-1-甲基环丁醇,OSI 906; OSI-906; OSI906) 目录号 : GC15749
Linsitinib是一种强效、选择性、具有口服生物利用度的IGF-1R/IR双激酶抑制剂，对IGF-1R和IR的IC50值分别为0.035μM和0.075μM。
Cas No.:867160-71-2
Sample solution is provided at 25 µL, 10mM.
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Linsitinib is a potent, selective, and orally bioavailable dual IGF-1R/IR kinase inhibitor, with the IC50 values of 0.035μM, and 0.075μM, respectively [1]. Linsitinib inhibits the autophosphorylation after binding of the cognate ligands to the IGF-1R and IR, and therefore blocks the IGF-I and IGF-II induced activation of downstream pathways, such as AKT and ERK signaling[2]. Linsitinib has been widely used in different cancer cell models and xenograft tumor models to inhibit tumor growth[3].
In vitro, Linsitinib treatment for 48h inhibited the proliferation of KYSE150 cells, KYSE450 cells, KYSE510 cells, and TE-7 cells with IC50 values of 22.42μM, 8.524μM, 15.83μM, and 5.669μM, respectively[4]. A 2-hour pretreatment with 20μM Linsitinib inhibited IGF-1-induced phosphorylation of IGF-1Rβ at Tyr1135, phosphorylation of Akt at Ser473, and phosphorylation of ERK in orbital fibroblasts (OFs), and reduced hyaluronic acid secretion[5]. Treatment of IGF-1R-expressing NCI-H295R cells with 31.6125μg/ml Linsitinib for 24h inhibited proliferation and induced apoptosis, accompanied by a significant increase in caspase-3/7 activity[6].
In vivo, Linsitinib treatment via oral administration at a dose of 60mg/kg/day for 10 days resulted in inhibition of tumor growth in NCI-H292 xenograft mice[7]. Intragastric administration of Linsitinib (50mg/kg/day) for 3 consecutive days significantly reduced seizure severity, prolonged seizure latency, and reduced electroencephalogram (EEG) power density in the lithium-pilocarpine rat model[8]. Intraperitoneal injection of Linsitinib (20mg/kg/day) 3 days before ischemia-reperfusion (IR) injury improved the survival of mice after renal IR injury and reduced tubulointerstitial damage and tubular necrosis[9].
References:
[1] Mulvihill M J, Cooke A, Rosenfeld-Franklin M, et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor[J]. Future medicinal chemistry, 2009, 1(6): 1153-1171.
[2] Wang Y J, Zhang Y K, Kathawala R J, et al. Repositioning of tyrosine kinase inhibitors as antagonists of ATP-binding cassette transporters in anticancer drug resistance[J]. Cancers, 2014, 6(4): 1925-1952.
[3] Ji Q S, Mulvihill M, Rosenfeld-Franklin M, et al. Preclinical characterization of OSI-906: a novel IGF-1R kinase inhibitor in clinical trials[J]. Molecular Cancer Therapeutics, 2007, 6(11_Supplement): C192-C192.
[4] Kang J, Guo Z, Zhang H, et al. Dual inhibition of EGFR and IGF-1R signaling leads to enhanced antitumor efficacy against esophageal squamous cancer[J]. International Journal of Molecular Sciences, 2022, 23(18): 10382.
[5] Lee J Y, Lee S B, Yang S W, et al. Linsitinib inhibits IGF-1-induced cell proliferation and hyaluronic acid secretion by suppressing PI3K/Akt and ERK pathway in orbital fibroblasts from patients with thyroid-associated ophthalmopathy[J]. Plos one, 2024, 19(12): e0311093.
[6] Luffy M, Ganz A L, Wagner S, et al. Linsitinib inhibits proliferation and induces apoptosis of both IGF-1R and TSH-R expressing cells[J]. Frontiers in Immunology, 2024, 15: 1488220.
[7] McKinley E T, Bugaj J E, Zhao P, et al. 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer[J]. Clinical Cancer Research, 2011, 17(10): 3332-3340.
[8] Jiang G, Wang S, Chen M, et al. Linsitinib (OSI-906) modulates brain energy metabolism and seizure activity in the lithium-pilocarpine rat model[J]. Acta Epileptologica, 2021, 3(1): 19.
[9] Lyon A, Agius T, Macarthur M R, et al. Dietary or pharmacological inhibition of insulin-like growth factor-1 protects from renal ischemia-reperfusion injury in mice[J]. iScience, 2024, 27(12).
Linsitinib是一种强效、选择性、具有口服生物利用度的IGF-1R/IR双激酶抑制剂，对IGF-1R和IR的IC50值分别为0.035μM和0.075μM[1]。Linsitinib通过抑制相应配体与IGF-1R和IR结合后的自身磷酸化，从而阻断IGF-I和IGF-II诱导的下游信号通路（如AKT和ERK）的激活[2]。Linsitinib已广泛应用于多种癌细胞模型和移植瘤模型中，以抑制肿瘤生长[3]。
在体外，Linsitinib处理48小时可抑制KYSE150、KYSE450、KYSE510和TE-7细胞的增殖，IC50值分别为22.42μM、8.524μM、15.83μM和5.669μM[4]。用20μM的Linsitinib预处理眼眶成纤维细胞(OFs)2小时，能抑制IGF-1诱导的IGF-1Rβ（Tyr1135位点）、Akt（Ser473位点）和ERK的磷酸化，并减少透明质酸的分泌[5]。使用31.6125μg/ml的Linsitinib处理表达IGF-1R的NCI-H295R细胞24小时，可抑制细胞增殖并诱导凋亡，伴随caspase-3/7活性显著升高[6]。
在体内，以60mg/kg/day的剂量口服Linsitinib 10天，能抑制NCI-H292移植瘤小鼠的肿瘤生长[7]。在锂-毛果芸香碱大鼠模型中，连续3天每日灌胃Linsitinib（50mg/kg/day）能显著降低癫痫发作严重程度、延长发作潜伏期，并降低脑电图功率密度[8]。在缺血再灌注损伤前3天，每日腹腔注射Linsitinib（20mg/kg/day），可提高小鼠肾缺血再灌注损伤后的存活率，并减轻肾小管间质损伤和肾小管坏死[9]。
| Cell experiment [1]: | |
Cell lines | TE-7 cells |
Preparation Method | TE-7 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum, 100units/ml penicillin, and 100μg/ml streptomycin. Cells were cultured in a 5% CO2 incubator at 37°C. TE-7 cells were seeded in 96-well plates and cultured for 24 hours. After 48 hours of treatment with various concentrations of Linsitinib (1, 2, 4, 6, 8, 10μM), 20μl MTT (5mg/ml) was added to each well and incubated for 4 hours at 37°C. Formazan was dissolved in 150μl DMSO, and the optical density at 570nm was then measured. |
Reaction Conditions | 1, 2, 4, 6, 8, 10μM; 48h |
Applications | Linsitinib treatment reduced the proliferation of TE-7 cells in a concentration-dependent manner. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6J mice |
Preparation Method | 10 to 12-week-old male C57BL/6J mice had ad libitum access to food and water and were housed under standard housing conditions with a 12-h light/12-h dark cycle, humidity of 30 to 70%, and temperature of 20°C-23°C. Two days before surgery and on the morning of surgery, Linsitinib (20mg/kg/day) was injected intraperitoneally every morning. Mice were anesthetized with 3% isoflurane in 2L O2 and kept at 37°C with an electrical heating pad. Following a 2-cm abdominal incision, the vascular pedicles of the right and left kidneys were identified under a microscope. First, the right renal artery, vein, and ureter were ligated and cauterized. The left pedicle was clamped for mice with vascular micro-clamps. The wound was closed, and the mouse tissues were collected for analysis on the second day after renal IR injury. |
Dosage form | 20mg/kg/day for 3 days; i.p. |
Applications | Linsitinib treatment significantly reduced IR injury in mice, inhibited histological tubulointerstitial damage, and tubular necrosis. |
References: | |
| Cas No. | 867160-71-2 | SDF | |
| 别名 | 顺式-3-[8-氨基-1-(2-苯基-7-喹啉基)咪唑并[1,5-A]吡嗪-3-基]-1-甲基环丁醇,OSI 906; OSI-906; OSI906 | ||
| 化学名 | 3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol | ||
| Canonical SMILES | CC1(CC(C1)C2=NC(=C3N2C=CN=C3N)C4=CC5=C(C=C4)C=CC(=N5)C6=CC=CC=C6)O | ||
| 分子式 | C26H23N5O | 分子量 | 421.51 |
| 溶解度 | ≥ 21.1mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3724 mL | 11.8621 mL | 23.7242 mL |
| 5 mM | 474.5 μL | 2.3724 mL | 4.7448 mL |
| 10 mM | 237.2 μL | 1.1862 mL | 2.3724 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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- Purity: >98.00%
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