Sapanisertib

Sapanisertib (INK-128, MLN0128) is a potent, ATP-competitive, orally active dual mTORC1/2 inhibitor with Ki of 1.4 nM in cell-free assays, >200-fold selectivity over calss I PI3K isoforms; inhibits both the phosphorylation of S6 and 4EBP1, the downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at Ser473, the downstream substrate of TORC2; also shows potent inhibition effects on cell lines resistant to rapamycin and pan-PI3K inhibitors; shows tumor growth inhibition efficacy in multiplexenograft models.Brain Cancer Phase 2 Clinical(In Vitro):Sapanisertib (INK-128) exhibits an enzymatic inhibition activity against mTOR and more than 100-fold selectivity to PI3K kinases. Sapanisertib (INK-128) selectively decreases the expression of YB1, MTA1, vimentin and CD44 at the protein but not transcript level in PC3 cells. Sapanisertib (INK-128) decreases the invasive potential of PC3 prostate cancer cells. Furthermore, Sapanisertib (INK-128) inhibits cancer cell migration starting at 6 h of treatment, precisely correlating with when decreases in the expression of pro-invasion genes are evident, but preceding any changes in the cell cycle or overall global protein synthesis.(In Vivo):In a ZR-75-1 breast cancer xenograft model, Sapanisertib (INK-128) shows tumor growth inhibition efficacy at a dose of 0.3 mg/kg/day. 4EBP1 and p70S6K1/2 phosphorylation is completely restored to wild-type levels after treatment with INK128 in PtenL/L mice. Sapanisertib (INK-128) treatment results in a 50% decrease in prostatic intraepithelial neoplasia (PIN) lesions in PtenL/L mice and induces programmed cell death in multiple cancer cell lines in mice.