| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg | |||
| 50mg | |||
| 100mg | |||
| 250mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
PIM1, PIM2, PIM3 kinases
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| ln Vitro |
With IC50 values ranging from 0.2 to 3.3 μM for sensitive cell lines (MM1S, MM1R, RPMI-8226, MM144, U266, and NCI-H929) and less sensitive cell lines (OPM-2, RPMI-LR5, U266-Dox4, and U266-LR7) with IC50 values >7 μM at 48 hours, PIM-447 dihydrochloride (0.05-10 μM; 24, 48, and 72 hours) is inhibitory to MM cells [1]. When PIM-447 dihydrochloride is at 5 μM, it significantly increases annexin-sensitive cell lines (MM1S, NCI-H929, and RPMI-8226) (approximately 30%), but it does not cause significant levels of apoptosis at concentrations of 0.1–10 μM over 24, 48, or 72 hours. PIM447 causes apoptosis in all cell lines at 10 μM, but it affects OPM-2 and RPMI-LR5 less severely [1]. In MM1S, RPMI-8226, and NCI-H929 cells, PIM447 increases cleavage of effector caspases 3 and 7, and promotes cleavage of initiating caspases, such as caspases 8 and 9. cutting with PARP [1]. PIM447 (0.1–1 μM) reduces the proliferation phase of the cell cycle (S and G2/M) and raises the proportion of cells in the G0/G1 phase. Compared to OPM-2, the impact of MM1S cells is more noticeable at low concentrations (0.1–1 μM) [1].
As the dihydrochloride salt of PIM447, this form exhibits the same potent inhibition of PIM1, PIM2, and PIM3 kinases as the parent compound, with Ki values of 6 pM, 18 pM, and 9 pM for PIM1, PIM2, and PIM3, respectively. The salt form may offer improved physicochemical properties such as solubility and stability compared to the free base. In cellular assays, the compound inhibits PIM kinase-mediated phosphorylation of downstream substrates and suppresses proliferation of PIM-dependent cancer cell lines. |
| ln Vivo |
In a mouse model of bone marrow disseminated human multiple myeloma, PIM447 (oral gavage; 100 mg/kg; 5 times/week) significantly controlled tumor progression and serum levels of hIgλ secreted by RPMI-8226-luc cells [1].
In vivo efficacy of PIM447 dihydrochloride is equivalent to that of the parent compound, demonstrating significant anti-tumor activity in xenograft models of hematological malignancies and solid tumors following oral administration. The salt form provides favorable pharmacokinetic properties with good oral bioavailability. Biomarker analyses confirm target engagement through inhibition of PIM kinase signaling in tumor tissues. |
| Enzyme Assay |
Kinase assays measure inhibition of PIM1, PIM2, and PIM3 enzymatic activity using radiometric or luminescent methods with recombinant enzymes and peptide substrates. IC50 values are determined from dose-response curves. Selectivity profiling confirms the compound's specificity for PIM kinases over other kinases in the kinome.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: Sensitive MM Cell Types: MM1S, MM1R, RPMI-8226, MM144, U266 and NCI-H929 cells Less sensitive MM Cell Types: OPM-2,RPMI-LR5, U266-Dox4 and U266- LR7cells Tested Concentrations: 0.05-10 µM Incubation Duration: 24, 48 and 72 hrs (hours) Experimental Results: Was cytotoxic for MM cells (PIM kinases highly expressed). Apoptosis Analysis[1] Cell Types: Sensitive MM Cell Types: MM1S, NCI-H929 and RPMI -8226 cells Less sensitive MM Cell Types: OPM-2 and RPMI-LR5 cells Tested Concentrations: 0.05-10 µM Incubation Duration: 24, 48 and 72 hrs (hours) Experimental Results: Induced cell apoptosis at higer doses, had no effects at 0.1-1 uM. Western Blot Analysis[1] Cell Types: Sensitive MM Cell Types: MM1S, NCI-H929 and RPMI-8226 cells Tested Concentrations: 0.05-10 µM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Increased the cleavage of the effector caspases 3 and 7, and the PARP cleavage. Cell Cycle Analysis[1] Cell Types: MM1S, OPM-2 cells Tested Concentrations: 0.1, 0.5 or 1 µM Incubation Duration: 48 hrs (hours) Experimental Results: Increased the cleavage of the effector ca Cellular potency is evaluated in cancer cell lines by measuring PIM kinase substrate phosphorylation (BAD, 4E-BP1, p27Kip1) using 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. The salt form demonstrates equivalent cellular activity to the parent compound. |
| Animal Protocol |
Animal/Disease Models: RPMI-8226-luc cells are injected intravenously (iv)into 6weeks old female NODSCID-IL-2Rγ-/-(NSG) mice[1]
Doses: 100 mg/kg Route of Administration: po (oral gavage); 100 mg/kg; 5 times/week Experimental Results: Was well tolerated, as the body weight of mice did not decrease by more than 10%. Increased bone volume density and trabecular number and decreased trabecular separation relative to vehicle group. In vivo efficacy is evaluated in mouse xenograft models of hematological malignancies and solid tumors. PIM447 dihydrochloride 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 dihydrochloride demonstrates excellent oral bioavailability and favorable pharmacokinetic properties in preclinical species, equivalent to the parent compound. The salt form may offer advantages in solubility and formulation. Detailed PK parameters including half-life, clearance, and volume of distribution are available from preclinical and clinical studies.
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| Toxicity/Toxicokinetics |
Toxicology data for PIM447 dihydrochloride are derived from the clinical development program of PIM447, indicating that the compound is generally well-tolerated at studied doses. Comprehensive toxicology assessments have been conducted as part of the clinical development process. Standard safety monitoring and adverse event reporting apply.
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| References |
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| Additional Infomation |
PIM447 dihydrochloride is the salt form used in pharmaceutical development and clinical studies of the pan-PIM inhibitor PIM447. The salt form may be preferred for formulation development due to improved physicochemical properties. The compound has been investigated in clinical trials for hematological malignancies and solid tumors, with development status varying.
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| Molecular Formula |
C24H25CL2F3N4O
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|---|---|---|
| Molecular Weight |
513.39
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| Exact Mass |
512.135
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| CAS # |
1820565-69-2
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| Related CAS # |
PIM447;1210608-43-7;(1S,3R,5R)-PIM447 dihydrochloride
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| PubChem CID |
122198133
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
34
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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.Cl.Cl
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| InChi Key |
BVRSHQQSBGCMJE-ALGQTRDQSA-N
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| InChi Code |
InChI=1S/C24H23F3N4O.2ClH/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);2*1H/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;dihydrochloride
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to 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: ≥ 2.5 mg/mL (4.87 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9478 mL | 9.7392 mL | 19.4784 mL | |
| 5 mM | 0.3896 mL | 1.9478 mL | 3.8957 mL | |
| 10 mM | 0.1948 mL | 0.9739 mL | 1.9478 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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