The serine/threonine Pim kinases have been suggested to promote the activity of the rapamycin-sensitive mammalian target of rapamycin (mTORC1), which regulates cell growth and survival. Pim kinases are overexpressed in solid cancers and hematologic malignancies, and as such have become targets of small molecule inhibitors to prevent the progression of various cancers. 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.
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