SMI-4a is a potent inhibitor of Pim1 with IC50 of 17 nM, modestly potent to Pim-2, does not significantly inhibit any other serine/threonine- or tyrosine-kinases.
Pim (provirus integration site for Moloney murine leukemia virus) family proteins are highly conserved serine/threonine kinases implicated in transcription, translation, cell cycle, survival, and drug resistance through the numerous targets. SMI-4a is a potent inhibitor of Pim1 with IC50 of 17 nM (measured by kinase activity assay), as well as shows modest potency to Pim-2. As BAD is a novel substrate of Pim-1, SMI-4a < 5 μM caused dose-dependent reduction of p-BAD in prostate and hematopoietic cells tested. Treatment with 5 μM SMI-4a for 72 h showed various degree of growth inhibition (10-40%) of PC3, DU145, LNCaP, U937, K562 and MV4;11 cells cultured in media containing 10% FBS. Because SMI-4a showed to be serum-bound, it was found that DU145 cells became considerably more sensitive under serum-free conditions. For many substrates of Pim-1 play a role in cell cycle progression, as prediction, treatment with 5 μM SMI-4a for 72 h caused a significant G1 cell cycle arrest of DU145 cells growing in 2% serum and MV4;11 cells plated in 10% serum, as well as a considerable amount of apoptosis (sub-G1 29.2%) of 22Rv1 cells cultured under serum starvation condition. The translocation of p27Kip1 to the nucleus and reduced Cdk2 activity (shown by decreased p-H1) can also observed in K562 cells cultured in RPMI containing 10% FCS after treatment with SMI-4a. SMI-4a can synergize with rapamycin to cause significant growth inhibition, as well as decreased phosphorylation level of 4E-BP1 of MV4;11 and FDCP1 (IL-3 dependent) cells[1]. Combination treatment of ABT-737 (50 mg/kg; i.p., QD) and SMI-4a (60 mg/kg, oral gavage, BID) for 16 days significantly reduce the tumor growth of LNCaP xenograft model[2].
作用机制
SMI-4a can compete with respect to ATP, suggesting that it may bind within the ATP-binding pocket of the kinase.[1]
SMI-4a 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
DLD-1 cell
Function assay
96 h
Inhibition of growth of DLD-1 cell line after 96 hours of exposure time with the compound dissolved in DMSO, IC50=17.8 μM
15993594
HCT116 cell
Function assay
72 h
Inhibition of growth of HCT116 cell line after 72 hours of exposure time with the compound dissolved in DMSO, IC50=48.8 μM
15993594
HEK293T cells
0.5 μM
Function assay
1 h
Inhibition of human recombinant Flag-Pim1 autophosphorylation expressed in HEK293T cells labeled with [32PO4] at 0.5 uM after 1hr by Western blotting
19072652
HT-29 cell
Function assay
Inhibition of growth of HT-29 cell line after 72+72 hours of exposure time with the compound dissolved in DMSO, IC50=31.4 μM
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