Sapanisertib (INK-128) demonstrates enzymatic inhibitory activity against mTOR with over 100-fold selectivity compared to PI3K kinases[1]. Sapanisertib (INK-128) selectively reduces the protein levels of YB1, MTA1, vimentin, and CD44 without affecting their mRNA levels in PC3 cells. It also diminishes the invasive capabilities of PC3 prostate cancer cells. Additionally, Sapanisertib (INK-128) impedes cancer cell migration beginning at 6 hours post-treatment, coinciding with the evident reduction in pro-invasion gene expression, and before any alterations in the cell cycle or overall global protein synthesis are observed[2].
体内研究
In a ZR-75-1 breast cancer xenograft model, Sapanisertib (INK-128) effectively inhibits tumor growth at a daily dose of 0.3 mg/kg[1].
Treatment with INK128 fully restores 4EBP1 and p70S6K1/2 phosphorylation to wild-type levels in PtenL/L mice. Additionally, Sapanisertib (INK-128) leads to a 50% reduction in prostatic intraepithelial neoplasia (PIN) lesions in PtenL/L mice and triggers programmed cell death across various cancer cell lines in mice[2].
体外研究
Sapanisertib (INK-128) demonstrates enzymatic inhibitory activity against mTOR with over 100-fold selectivity compared to PI3K kinases[1].
Sapanisertib (INK-128) selectively reduces the protein levels of YB1, MTA1, vimentin, and CD44 without affecting their mRNA levels in PC3 cells. It also diminishes the invasive capabilities of PC3 prostate cancer cells. Additionally, Sapanisertib (INK-128) impedes cancer cell migration beginning at 6 hours post-treatment, coinciding with the evident reduction in pro-invasion gene expression, and before any alterations in the cell cycle or overall global protein synthesis are observed[2].
Sapanisertib/沙帕色替 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BON cells
100 nM
48 h
Sapanisertib inhibited mTOR signaling and suppressed TF levels.
J Thromb Haemost. 2019 Jan;17(1):169-182.
BON cells
100 nM
48 h
To evaluate the effect of Sapanisertib on TF expression, results showed that Sapanisertib significantly reduced TF mRNA and protein expression.
J Thromb Haemost. 2019 Jan;17(1):169-182.
Human cutaneous melanoma cells (WM3311, WM2032, WM853–2, WM858)
40 nM
72 h
To evaluate the cytotoxicity of Sapanisertib on human cutaneous melanoma cells, results showed reduced cell survival.
Mol Cancer Ther. 2020 Nov;19(11):2308-2318.
Canine MM cells (M1, M5, M2, M3, Jones)
40 nM
4 and 24 h
To evaluate the inhibitory effect of Sapanisertib on the PI3K/mTOR signaling pathway, results showed reduced levels of p-AKT and p-S6.
Mol Cancer Ther. 2020 Nov;19(11):2308-2318.
H460
2μM
24 or 48 h
MLN0128 durably inhibited HIF1α and GLUT1 expression and reduced glucose metabolism.
Cancer Res. 2015 Nov 15;75(22):4910-22.
A549
2μM
24 h
MLN0128 significantly inhibited mTORC1 and mTORC2 signaling pathways and induced apoptosis.
Cancer Res. 2015 Nov 15;75(22):4910-22.
SK-BR-3
0.2 μM
24 h
To evaluate the effect of Sapanisertib in combination with Neratinib on downstream signaling pathways in HER2+ cells. Results showed that Sapanisertib combined with Neratinib significantly inhibited phosphorylation of 4E-BP1 and S6.
Clin Cancer Res. 2021 Mar 15;27(6):1681-1694.
BT-474
0.2 μM
24 h
To evaluate the effect of Sapanisertib in combination with Neratinib on downstream signaling pathways in HER2+ cells. Results showed that Sapanisertib combined with Neratinib significantly inhibited phosphorylation of 4E-BP1 and S6.
Clin Cancer Res. 2021 Mar 15;27(6):1681-1694.
HCC-1954
0.2 μM
24 h
To evaluate the effect of Sapanisertib in combination with Neratinib on downstream signaling pathways in HER2+ cells. Results showed that Sapanisertib combined with Neratinib significantly inhibited phosphorylation of 4E-BP1 and S6.
Clin Cancer Res. 2021 Mar 15;27(6):1681-1694.
Bone marrow cells
0 nM, 25 nM, 50 nM, 100 nM
4 days
To investigate the effect of INK128 on the accumulation of MDSCs, results showed that INK128 inhibited the accumulation of MDSCs.
Stem Cell Res Ther. 2021 Mar 10;12(1):170.
Sapanisertib/沙帕色替 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
SHH-driven medulloblastoma model
Intraperitoneal injection
0.1 mg/kg or 0.2 mg/kg
Daily or every other day until P35
To test the efficacy of combining Sapanisertib with Palbociclib, results showed that the combination significantly prolonged mouse survival and reduced recurrence during therapy.
Sci Adv. 2022 Jan 28;8(4):eabl5838
Nude mice
BON tumor model
Oral gavage
3 mg/kg
Every other day for 34 days
To evaluate the effect of Sapanisertib on BON tumor growth, results showed that Sapanisertib significantly reduced tumor volume and TF protein expression.
J Thromb Haemost. 2019 Jan;17(1):169-182.
Nude mice
Canine MM xenograft model
Oral
2.0 mg/kg
Every other day for 3 weeks
To evaluate the tumor growth inhibitory effect of Sapanisertib on the canine MM xenograft model, results showed inhibited tumor growth.
Mol Cancer Ther. 2020 Nov;19(11):2308-2318.
Mice
KL luc mice
Intraperitoneal injection
1.0mg/kg
Once daily for 5 days
MLN0128 potently inhibited mTORC1 and mTORC2 signaling pathways and reduced glucose metabolism.
Cancer Res. 2015 Nov 15;75(22):4910-22.
Mice
Diabetic mice model
Intraperitoneal injection
1 mg/kg
Once daily for 45 days
To investigate the effect of INK128 on wound healing in diabetic mice, results showed that INK128 promoted wound healing.
Stem Cell Res Ther. 2021 Mar 10;12(1):170.
Nude mice
Orthotopic neuroblastoma xenograft model
Intraperitoneal injection
2 mg/kg
Once daily for 28 days
INK128 significantly inhibited tumor growth in the orthotopic neuroblastoma xenograft model
Apoptosis. 2015 Jan;20(1):50-62
Nude mice
BON tumor model
Oral gavage
3 mg/kg
Every other day for 35 days
Sapanisertib significantly reduced TF protein and co-factor activity in BON tumors, and the tumors were smaller compared to those in control mice.
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