OSI-027 is a selective small molecule oral inhibitor that can simultaneously inhibit the kinase activities of mTORC1 and mTORC2, with IC50 values of 22nM and 65nM, respectively[1]. OSI-027 blocks mTORC1/2 activation, and results in the downregulation of phosphor-Akt, phpspho-p70S6k, phosphor-4EBP1, cyclin D1, and cyclin-dependent kinase4 (CDK4)[2]. OSI-027 has been widely used as an anti-cancer agent to inhibit tumor growth in animal models of xenografts[3].
In vitro, OSI-027 treatment for 24 hours significantly reduced the cell viability of Panc-1, BxPC-3 and CFPAC-1 cells, with IC50 values were 21.57μM, 8.360μM and 13.72μM, respectively[4]. Treatment with 10μM OSI-027 for 48 hours induced apoptosis in HCT116 and SW620 cells, significantly up-regulating the protein levels of Bax, Bim, cleaved-caspase 3, FOXO3a and PUMA in colon cancer cells[5]. Treatment with 4μM OSI-027 for 48 hours induced cell cycle arrest in Hep-3B cells and inhibited the phosphorylation of mTORC1 substrates in Hep-3B cells, including 4E-BP1 (Thr37/46) and p70S6K (Thr389)[6].
In vivo, OSI-027 treatment via intraperitoneal injection at a dose of 0.5mg/kg (three times a week) for two consecutive weeks significantly reduced inflammation in the alveolar cavities and alveolar septa, and alleviated lung injury and fibrosis in the models of lung injury in juvenile rats caused by hyperoxia[7]. Daily intraperitoneal injection of 10mg/kg dose of OSI-027 and 5mg/kg dose of SB202190 for 12 days can significantly inhibit tumor growth in mice with xenografted SW620 tumors and induce apoptosis of tumor cells[8].
References:
[1] Gokhale P C, Bhagwat S V, Crew A P, et al. OSI-027, a selective dual mTORC1/TORC2 kinase inhibitor displays broad spectrum anti-tumor activity in preclinical models of human cancer[J]. Cancer Research, 2010, 70(8_Supplement): 4486-4486.
[2] Xu E, Zhu H, Wang F, et al. OSI-027 alleviates oxaliplatin chemoresistance in gastric cancer cells by suppressing P-gp induction[J]. Current Molecular Medicine, 2021, 21(10): 922-930.
[3] Chen B W, Xiong J N, Zhi X, et al. WZ4003 sensitizes hepatocellular carcinoma to OSI-027 by inhibiting ARK5-mediated autophagy[J]. Cancer Letters, 2025: 217989.
[4] Zhi X, Chen W, Xue F, et al. OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo[J]. Oncotarget, 2015, 6(28): 26230.
[5] Lou J, Lv J X, Zhang Y P, et al. OSI‐027 inhibits the tumorigenesis of colon cancer through mediation of c‐Myc/FOXO3a/PUMA axis[J]. Cell Biology International, 2022, 46(8): 1204-1214.
[6] Chen B W, Chen W, Liang H, et al. Inhibition of mTORC2 induces cell-cycle arrest and enhances the cytotoxicity of doxorubicin by suppressing MDR1 expression in HCC cells[J]. Molecular cancer therapeutics, 2015, 14(8): 1805-1815.
[7] Liang M, Dang H, Li Q, et al. Effects of rapamycin and OSI-027 on α-SMA in lung tissue of SD rat pups with hyperoxic lung injury[J]. Biochemical and Biophysical Research Communications, 2021, 556: 39-44.
[8] Zhang Y, Wang X, Qin X, et al. PP2AC level determines differential programming of p38-TSC-mTOR signaling and therapeutic response to p38-targeted therapy in colorectal cancer[J]. EBioMedicine, 2015, 2(12): 1944-1956.
OSI-027是一种选择性小分子口服抑制剂，可同时抑制mTORC1和mTORC2的激酶活性，IC50值分别为22nM和65nM[1]。OSI-027能阻断mTORC1/2的激活，导致磷酸化Akt、磷酸化p70S6k、磷酸化4EBP1、细胞周期蛋白D1以及cyclin-dependent kinase4 (CDK4)的表达下调[2]。OSI-027 已作为一种抗癌剂，广泛用于抑制异种移植动物模型中的肿瘤生长[3]。
在体外，OSI-027处理24小时显著降低了Panc-1、BxPC-3和CFPAC-1细胞的细胞活力，IC50值分别为21.57μM、8.360μM和13.72μM[4]。用10μM的OSI-027处理48小时诱导了HCT116和SW620细胞的凋亡，显著上调了细胞中Bax、Bim、cleaved-caspase 3、FOXO3a和PUMA的蛋白水平[5]。用4μM的OSI-027处理48小时诱导了Hep-3B细胞的细胞周期阻滞，并抑制了Hep-3B细胞中mTORC1底物的磷酸化，包括4E-BP1（Thr37/46）和p70S6K（Thr389）[6]。
在体内，OSI-027以0.5mg/kg剂量（每周三次）腹腔注射连续两周，显著减少了高氧诱导的幼年大鼠肺损伤模型中肺泡腔和肺泡间隔的炎症，减轻了肺损伤和纤维化[7]。每日腹腔注射10mg/kg剂量的OSI-027和5mg/kg剂量的SB202190连续12天，可显著抑制异种移植SW620肿瘤小鼠的肿瘤生长并诱导肿瘤细胞凋亡[8]。