SMI-4a

Catalog No.S8005

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.

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SMI-4a Chemical Structure

SMI-4a Chemical Structure
Molecular Weight: 273.23

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description 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.
Targets Pim1 [1]
IC50 17 nM
In vitro SMI-4a is an ATP competitive inhibitor of Pim1 with IC50 of 17 nM. SMI-4a shows high selectivity for Pim1 against a panel of kinases. SMI-4a inhibits the in vitro phosphorylation by Pim-1 of the known substrate, the translational repressor 4E-BP1. SMI-4a (5μM) inhibits pancreatic and leukemic cells growth. SMI-4a reduces phosphorylation of the Pim target Bad in prostate and hematopoietic cells. SMI-4a causes cell cycle arrest and reverses the antiapoptotic activity of Pim-1. SMI-4a increases the amount of p27Kip1 in the nucleus.[1] SMI-4a treatment of pre-T-LBL inhibits the mTOR pathway. SMI-4a reduces MYC protein expression in pre-T-LBL. SMI-4a treatment induces up-regulation of MAPK pathway. [2]
In vivo SMI-4a (60 mg/Kg) treatment twice daily significantly reduce tumor size and is well tolerated. Tumors harvested 1 hour after the final oral gavage of SMI-4a demonstrates decreased phosphorylation of p70 S6K compared with tumors from mice treated with vehicle, whereas in comparison total p70 S6K expression isunchanged. [2]
Features SMI-4a (5μM) synergizes with rapamycin (5 nM) to cause significant growth inhibition of leukemic cells.

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase Activity Assay IC50 values for Pim inhibitors are measured by a coupled kinase assay as described previously with the following changes: assays are carried out in 20 mM MOPS containing 100 mM NaCl, 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 0.2 mM NADH, 30μg/mL pyruvate kinase, 10μg/mL lactate dehydrogenase, 2 mM DTT, and 25 nM Pim-1 with 100μM peptide. Activity ismeasured by monitoring NADH oxidation as the decrease at 340 nm in a VersaMax microplate reader at 25 ℃. Reactions are initiated by the addition of ATP (100 μM), and inhibitors (final 1% DMSO) are added just before the addition of ATP. IC50 values are determined using nonlinear regression with the program GraphPad Prism. This assay determines kinase activity by measuring the amount of ADP produced, which is coupled to NADH oxidation by lactate dehydrogenase and pyruvate kinase. The ability of Pim-1 kinase to phosphorylate full-length protein substrates 4E-BP1 and p27Kip1 isdetermined as follows: purified Pim-1 (1 ng) isadded along with 4E-BP1 (2 μg) or p27Kip1 (2 μg) and Pim inhibitor in assay buffer [20 mM MOPS (pH 7) containing 100 mM NaCl, 10 mM MgCl2, and 2 mM DTT]. Assays are initiated by the addition of ATP (100 μM) and [γ-32P]ATP (10 μCi). Reactions are allowed to proceed for 15 min at 30℃ and then separated by SDS-PAGE. 32P-phosphorylated substrates are visualized by autoradiography and quantified by densitometry.

Animal Study: [2]

Animal Models Nu/nu nude mice injected with pre-T-LBL cells
Formulation In 65% DMSO, 30% PEG-400, 5% Tween-80
Dosages 60 mg/Kg
Administration p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Beharry Z, et al. Mol Cancer Ther, 2009, 8(6), 1473-1483.

[2] Lin YW, et al. Blood, 2010, 115(4), 824-833.

Chemical Information

Download SMI-4a SDF
Molecular Weight (MW) 273.23
Formula

C11H6F3NO2S

CAS No. 438190-29-5
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms TCS PIM-1 4a
Solubility (25°C) * In vitro DMSO 55 mg/mL (201.29 mM)
Ethanol 32 mg/mL (117.11 mM)
Water <1 mg/mL
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2,4-Thiazolidinedione, 5-[[3-(trifluoromethyl)phenyl]methylene]-, (5Z)-

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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