| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
PIM1, PIM2, PIM3 kinases
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| ln Vitro |
On multiple myeloma (MM) cells, PIM447 (0.05–10 μM; 24-72 hours) exhibits an antiproliferative effect[2]. Apoptosis is induced by PIM447 (10 μM; 6-24 hours)[2]. In the two cell lines (MM1S and OPM-2 cells), PIM447 (0.1–10 μM; 48 hours) reduces the proliferative phases (S and G2–M) of the cell cycle and raises the percentage of cells in the G0-G1 phase[2].
PIM447 demonstrates potent inhibition of PIM kinases with Ki values of 6 pM, 18 pM, and 9 pM for PIM1, PIM2, and PIM3, respectively. It also inhibits GSK3β. The compound shows excellent selectivity over other kinases in the kinome. It inhibits PIM kinase-mediated phosphorylation of downstream substrates including BAD, 4E-BP1, and p27Kip1. In cellular assays, PIM447 inhibits proliferation of various cancer cell lines, particularly those dependent on PIM kinase activity for survival and growth. PIM447 is cytotoxic for myeloma cells due to cell cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of the mTORC1 pathway. |
| ln Vivo |
Tumor burden is decreased by PIM447 (100 mg/kg; po; 5 times per week)[2].
In vivo, PIM447 demonstrates anti-tumor efficacy in multiple xenograft models of hematological malignancies and solid tumors. Oral administration of PIM447 results in significant tumor growth inhibition in a dose-dependent manner. The compound shows favorable pharmacokinetic properties with good oral bioavailability and tissue distribution. Biomarker analysis confirms target engagement through inhibition of PIM kinase signaling pathways in tumor tissues. |
| Enzyme Assay |
Kinase activity is measured using radiometric or luminescent kinase assays with recombinant PIM1, PIM2, and PIM3 enzymes and appropriate peptide substrates. IC50 values are determined from dose-response curves. Selectivity profiling is conducted against a panel of kinases to establish the selectivity profile. Binding affinity is assessed using surface plasmon resonance or competition binding assays.
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| Cell Assay |
Cell Viability Assay[2]
Cell Types: MM1S, MM1R, RPMI-8226, MM144, U266, NCI-H929, OPM-2, RPMI-LR5, U266-Dox4, and U266-LR7 cells Tested Concentrations: 0.05, 0.1, 0.5, 1, 5, 10 μM Incubation Duration: 24, 48, 72 hrs (hours) Experimental Results: Sensitive cell lines with IC50 values at 48 hrs (hours) ranging from 0.2 to 3.3 μM (MM1S, MM1R, RPMI-8226, MM144, U266, and NCI-H929 ) and less sensitive cell lines with IC50 values at 48 hrs (hours) >7 μmol/L (OPM-2, RPMI-LR5, U266-Dox4, and U266-LR7). Western Blot Analysis[2] Cell Types: MM1S cells Tested Concentrations: 10 μM Incubation Duration: 6, 12, 24 hrs (hours) Experimental Results: Promoted the cleavage of initiator caspases, such as caspases 8 and 9, and also the cleavage of the effector caspases 3 and 7, together with PARP cleavage. Cellular potency is evaluated in cancer cell lines by measuring PIM kinase substrate phosphorylation (BAD, 4E-BP1, p27Kip1) by Western blot. Cell proliferation is assessed using MTT, CellTiter-Glo, or BrdU incorporation assays. Apoptosis induction is measured by flow cytometry with annexin V/PI staining or by caspase activity assays. |
| Animal Protocol |
Animal/Disease Models: 6weeks old female NOD-SCID-IL-2Rγ−/− (NSG) mice (bearing RPMI-8226 -luc cells)[2]
Doses: 100 mg/kg Route of Administration: po; 5 times for a week Experimental Results: Clearly controlled tumor progression as measured by bioluminescence. In vivo efficacy is evaluated in mouse xenograft models of hematological malignancies and solid tumors. PIM447 is administered orally at various doses. Tumor growth inhibition is measured over time. Pharmacodynamic markers including phosphorylation of PIM substrates are assessed in tumor tissues. Pharmacokinetic sampling is performed to correlate exposure with efficacy. |
| ADME/Pharmacokinetics |
PIM447 demonstrates excellent oral bioavailability and favorable pharmacokinetic properties in preclinical species. The compound shows good tissue distribution and achieves therapeutic concentrations in tumor tissues. Detailed PK parameters including half-life, clearance, volume of distribution, and bioavailability are available from preclinical studies and clinical trials.
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| Toxicity/Toxicokinetics |
PIM447 has been evaluated in clinical trials for hematological malignancies and solid tumors. Safety data from these trials indicate that the compound is generally well-tolerated at studied doses. Comprehensive toxicology data are available from the clinical development program including assessments of genotoxicity, cardiotoxicity, and repeated-dose toxicity. Standard adverse event monitoring and dose-limiting toxicity assessments have been conducted.
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| References |
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| Additional Infomation |
LGH-447 is currently undergoing clinical trial NCT02160951 (LGH447 dose-escalation study in Japanese patients with relapsed and/or refractory hematologic malignancies). LGH447, a PIM kinase inhibitor, is an orally administered pan-PIM protein kinase inhibitor with potential antitumor activity. LGH447 binds to and inhibits the activity of PIM-1, -2, and -3 serine/threonine kinases, which may lead to G1/S phase cell cycle disruption, expression of the pro-apoptotic protein Bcl2, and apoptosis in PIM-overexpressing tumor cells. PIM kinases are downstream effector molecules in many cytokine and growth factor signaling pathways, playing a crucial role in cell cycle progression and apoptosis inhibition, and are likely overexpressed in various malignancies.
PIM447 has been investigated in clinical trials for multiple myeloma, acute myeloid leukemia, and other PIM-dependent cancers. The compound represents a promising therapeutic approach for targeting PIM kinases in cancer. Development status may vary, and the compound remains an important tool for studying PIM kinase biology and for therapeutic development in oncology. |
| Molecular Formula |
C24H23F3N4O.HCL
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|---|---|---|
| Molecular Weight |
476.92
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| Exact Mass |
440.182
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| CAS # |
1210608-43-7
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| Related CAS # |
PIM-447 dihydrochloride;1820565-69-2;(1S,3R,5R)-PIM447 dihydrochloride
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| PubChem CID |
44814409
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
493.7±45.0 °C at 760 mmHg
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| Flash Point |
252.4±28.7 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.593
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| LogP |
5.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
630
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| Defined Atom Stereocenter Count |
3
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| SMILES |
C[C@H]1C[C@H](C[C@H](C1)N)C2=C(C=NC=C2)NC(=O)C3=NC(=C(C=C3)F)C4=C(C=CC=C4F)F
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| InChi Key |
VRQXRVAKPDCRCI-ZNMIVQPWSA-N
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| InChi Code |
InChI=1S/C24H23F3N4O/c1-13-9-14(11-15(28)10-13)16-7-8-29-12-21(16)31-24(32)20-6-5-19(27)23(30-20)22-17(25)3-2-4-18(22)26/h2-8,12-15H,9-11,28H2,1H3,(H,31,32)/t13-,14+,15-/m0/s1
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| Chemical Name |
N-[4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 88 mg/mL (184.5 mM)
Water: 1 mg/mL (Insoluble) Ethanol: 88 mg/mL (184.5 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 5 mg/mL (11.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (50.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0968 mL | 10.4839 mL | 20.9679 mL | |
| 5 mM | 0.4194 mL | 2.0968 mL | 4.1936 mL | |
| 10 mM | 0.2097 mL | 1.0484 mL | 2.0968 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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