Temsirolimus

Temsirolimus is an inhibitor of ribosomal protein S6 phosphorylation and inhibits cell growth and clonogenic survival of cells in a concentration-dependent manner. Temsirolimus is a potent inhibitor of proliferation and induces apoptosis in primary human lymphoblastic leukemia (ALL) cells. Temsirolimus is a potent inhibitor of mTOR (FRAP) kinase activity with IC₅₀ of 1.76 μM in the absence of FKBP12, similar to that of rapamycin (IC₅₀ of 1.74 μM). Temsirolimus treatment at nanomolar concentrations (10 nM to <5 μM) displays a modest and selective antiproliferative activity via FKBP12-dependent mechanism, but can completely inhibit the proliferation of a broad panel of tumor cells at low micromolar concentrations (5-15 μM), involving FKBP12-independent suppression of mTOR (FRAP) signaling. Temsirolimus treatment causes a marked decline in global protein synthesis and disassembly of polyribosomes, accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2A, at micromolar but not nanomolar concentrations (20 μM).