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.