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]。