Sapanisertib is an Orally Active mTOR1/2 Inhibitor for Prostate Cancer Research

mTOR, the mammalian target of rapamycin, is a conserved serine/threonine kinase. mTOR often serves as a catalytic subunit and consists of two protein complexes: mTOR complex 1 and mTOR complex 2. The mTOR complex (mTORC) coordinates cell growth and division. According to research, mTOR promotes the migration and invasion of prostate cancer cells through translation-regulated gene signals. Here we introduce an mTOR ATP site inhibitor, Sapanisertib (INK-128), which can effectively inhibit prostate cancer metastasis.

Sapanisertib reprograms prostate cancer metastasis genes, and inhibits cancer cell metastasis.

Sapanisertib (INK-128) is an orally active ATP-dependent mTOR1/2 inhibitor with an IC₅₀ of 1 nM for mTOR kinase. Moreover, it (200 nM; 48 h) selectively reduces protein expression of the mTOR-sensitive invasion genes in PC3 cells, such as YB1, MTA1, vimentin, and CD44. On one hand, it reduces the invasive potential of PC3 prostate cancer cells, inhibits cell proliferation, and induces apoptosis. In addition, Sapanisertib began to inhibit cancer cell migration 6 hours after treatment, accompanied by a significant decrease in the expression of pro-invasive genes. This process precedes any changes in the cell cycle or overall protein synthesis.

Significantly, Sapanisertib completely inhibits mTOR in vivo, and prevents prostate cancer invasion and metastasis. Firstly, it suppresses tumor growth at a dose of 0.3 mg/kg/day (oral gavage) in the ZR-75-1 breast cancer xenograft model. And then, (0.3 mg/kg/day, 1 mg/kg/day; po) inhibits 4EBP1 and p70S6K1/2 phosphorylation in Pten^L/L mice, to wild-type levels. Finally, Sapanisertib reduces prostatic intraepithelial neoplasia (PIN) lesions by 50% in Pten^L/L mice and induces apoptosis in multiple cancer cell lines in mice.

In summary, Sapanisertib can directly reprogram mTOR-dependent pro-invasive gene expression and prostate cancer metastasis in vivo, and can be effectively used in clinical research of prostate cancer.

References:

[1]. Liu A, et al. Drug Discovery Today: Therapeutic Strategies. 2009, 6(2), 47-55. 

[2]. Hsieh AC, et al. Nature. 2012 Feb 22;485(7396):55-61.