tcsc1001 (Z) -SMI-4a

(Z)-SMI-4a is a selective ATP-competitive Pim-1 kinase inhibitor with an IC50 of 21 nM for Pim-1 compared to an IC50 of 100 nM for Pim-2 and with little or no activity against a panel of 50 other kinases tested.

IC50 value: 21 nM (Pim1); 100 nM (Pim2) [1]

Target: Pim-1

in vitro: Incubation of pre-T-LBL cells with (Z)-SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with (Z)-SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of (Z)-SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells [1]. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor (Z)-SMI-4a in Abl-transformed cells [2].

in vivo: In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with (Z)-SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries [1].