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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
OCI-Ly10 cells
40 μM
In all cell lines, SMI4a caused a marked reduction in cell number and viability.
Mol Cancer. 2015 Dec 8;14:205.
OCI-Ly3 cells
40 μM
In all cell lines, SMI4a caused a marked reduction in cell number and viability.
Mol Cancer. 2015 Dec 8;14:205.
Raji cells
40 μM
In all cell lines, SMI4a caused a marked reduction in cell number and viability.
Mol Cancer. 2015 Dec 8;14:205.
Ramos cells
40 μM
In all cell lines, SMI4a caused a marked reduction in cell number and viability.
Mol Cancer. 2015 Dec 8;14:205.
MCF-7/TaxR cells
5 nM
2 days
To investigate the effect of SMI-4a on paclitaxel-resistant cells, the results showed that the combination of paclitaxel and SMI-4a synergistically inhibited the growth of MCF-7/TaxR cells.
Oncogene. 2018 Nov;37(45):5997-6009.
Mouse bone marrow-derived macrophages (BMDMs)
3.3 μM, 10 μM, 30 μM
2 h
SMI-4a inhibited NLRP3 inflammasome activation, dose-dependently suppressing the cleavage of pro-IL-1β and pro-caspase-1.
Inhibition of PIM1 reduced the proportion of Th1 and Th17 cells and increased the proportion of Treg cells, attenuating the pathogenicity of CD4+ T cells.
Nat Commun. 2022 Oct 4;13(1):5866.
HEK293T cells
0.1 μM
30 min
To evaluate the inhibitory effect of SMI-4a on PIM1 kinase and its impact on GSK-3 kinase activity. The results showed that SMI-4a effectively inhibited PIM1 kinase activity, thereby preventing GSK-3 phosphorylation at the S10 site.
PLoS Pathog. 2012;8(10):e1002972.
SMI-4a 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
MCF-7/TaxR xenograft model
Intraperitoneal injection
60 mg/kg
Three times per week for two weeks
To investigate the effect of SMI-4a on paclitaxel-resistant tumors, the results showed that the combination of paclitaxel and SMI-4a significantly inhibited the growth of MCF-7/TaxR tumors.
Oncogene. 2018 Nov;37(45):5997-6009.
Mice
Experimental Autoimmune Uveitis (EAU) model
Oral
60 mg/kg
Once daily for 14 consecutive days
Inhibition of PIM1 significantly alleviated EAU symptoms, reduced the proportion of Th1 and Th17 cells, and increased the proportion of Treg cells.
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