In vitro
PP242, a potent mTOR kinase inhibitor, can inhibit mTOR with IC50 of 8 nM. PP242 disrupt leukemia/stroma interactions, which can promote survival of AML cells, and lead to apoptosis in AML cells cocultured with stroma. PP242 attenuated the activities of mTORC1 and mTORC2, sequentially inhibited phosphorylated AKT, S6K, and 4EBP1, and concurrently suppressed chemokine receptor CXCR4 expression in primary leukemic cells and in stromal cells cultured alone or cocultured with leukemic cells. PP242 can overcome feedback activation of AKT in multiple myeloma (MM) cells, but ERK activation induced by PP242 is still a problem.
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