SMI--4a

SIM-4a is a Pim kinase inhibitor that blocks mTORC1 activity via activation of AMPK. SIM-4a kills a wide range of both myeloid and lymphoid cell lines (with IC50 values ranging from 0.8 to 40 μM). Incubation of precursor T-cell lymphoblastic leukemia/lymphoma cells with 10 μM SMI-4a induces G1 phase cell-cycle arrest, dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mTORC1 pathway. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with 60 mg/kg SMI-4a causes a significant delay in the tumor growth.