SMI-4a

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.¹ 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.¹ SIM-4a kills a wide range of both myeloid and lymphoid cell lines (with IC₅₀ values ranging from 0.8 to 40 μM).² 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.² 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.²

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1. Beharry, Z., Mahajan, S., Zemskova, M., et al. The Pim protein kinases regulate energy metabolism and cell growth. Proc. Natl. Acad. Sci. USA 108(2), 528-533 (2011).

2. Lin, Y.W., Beharry, Z.M., Hill, E.G., et al. A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood 115(4), 824-833 (2010).