[CAS NO. 1820565-69-2] PIM-447dihydrochloride
PRODUCTS SPECIFICATIONS [1820565-69-2]
DESCRIPTION [1820565-69-2]
Overview
| MDL | MFCD30489747 |
|---|---|
| Molecular Weight | 513.38 |
| Molecular Formula | C24H25Cl2F3N4O |
| SMILES | O=C(C1=NC(C2=C(F)C=CC=C2F)=C(F)C=C1)NC3=C([C@H]4C[C@@H](N)C[C@@H](C)C4)C=CN=C3.Cl.Cl |
2 Publications Citing Use of MCE
Summary
PIM447 dihydrochloride (LGH447 dihydrochloride) is a potent, orally available, and selective pan- PIM kinase inhibitor, with K i values of 6, 18, and 9 pM for PIM1 , PIM2 , and PIM3 , respectively. PIM447 dihydrochloride displays dual antimyeloma and bone-protective effects. PIM447 dihydrochloride induces apoptosis [1] [2] .
IC50 & Target
Ki: 6 pM (PIM1); 18 pM (PIM1); 9 pM (PIM3) [1]
In Vitro
PIM-447 (0.05-10 µM; 24, 48 and 72 hours) has inhibitory effects in MM cells, it against sensitive cell lines with IC
50
values ranging from 0.2 to 3.3 µM (MM1S, MM1R, RPMI-8226, MM144, U266 and NCI-H929) and less sensitive cell lines with IC
50
values at 48 h >7 µM (OPM-2, RPMI-LR5, U266-Dox4 and U266-LR7)
[1]
.
PIM-447 (0.1-10 µM; 24, 48 and 72 hours) does not induce important levels of apoptosis, when PIM447 at 5 µM, it substantially increases annexin-V levels (about 30%) in sensitive cell lines(MM1S, NCI-H929 and RPMI-8226). When PIM447 at 10 µM, it induces apoptosis in all the cell lines but to a lesser extent in OPM-2 and RPMI-LR5
[1]
.
PIM447 promotes the cleavage of initiator caspases, such as caspases 8 and 9, and increases the cleavage of the effector caspases 3 and 7, together with PARP cleavage in MM1S,RPMI-8226 and NCI-H929 cells
[1]
.
PIM447 (0.1-1 µM) increases the percentage of cells in the G0/G1 phase and decreases the proliferative phases (S and G2/M) of the cell cycle. The effects at low concentrations (0.1-1 µM) were more pronounced in MM1S cells than in OPM-2
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Viability Assay [1]
| Cell Line: |
Sensitive MM cell lines: MM1S, MM1R, RPMI-8226, MM144, U266 and NCI-H929 cells
Less sensitive MM cell lines: OPM-2,RPMI-LR5, U266-Dox4 and U266-LR7cells |
| Concentration: | 0.05-10 µM |
| Incubation Time: | 24, 48 and 72 hours |
| Result: | Was cytotoxic for MM cells (PIM kinases highly expressed). |
Apoptosis Analysis [1]
| Cell Line: |
Sensitive MM cell lines: MM1S, NCI-H929 and RPMI-8226 cells
Less sensitive MM cell lines: OPM-2 and RPMI-LR5 cells |
| Concentration: | 0.05-10 µM |
| Incubation Time: | 24, 48 and 72 hours |
| Result: | Induced cell apoptosis at higer doses, had no effects at 0.1-1 uM. |
Western Blot Analysis [1]
| Cell Line: |
Sensitive MM cell lines: MM1S, NCI-H929 and RPMI-8226 cells
|
| Concentration: | 0.05-10 µM |
| Incubation Time: | 24, 48 hours |
| Result: | Increased the cleavage of the effector caspases 3 and 7, and the PARP cleavage. |
Cell Cycle Analysis [1]
| Cell Line: | MM1S, OPM-2 cells |
| Concentration: | 0.1, 0.5 or 1 µM |
| Incubation Time: | 48 hours |
| Result: | Increased the cleavage of the effector caspases 3 and 7, and the PARP cleavage. |
In Vivo
PIM447 (oral gavage; 100 mg/kg; 5 times/week) clearly controlls tumor progression and the serum levels of hIgλ secreted by RPMI-8226-luc cells in mouse model of bone marrow-disseminated human multiple myeloma
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | RPMI-8226-luc cells are injected intravenously into 6-week-old female NODSCID-IL-2Rγ -/- (NSG) mice [1] |
| Dosage: | 100 mg/kg |
| Administration: | oral gavage; 100 mg/kg; 5 times/week |
| Result: |
Was well tolerated, as the body weight of mice did not decrease by more than 10%.
Increased bone volume density and trabecular number and reduced trabecular separation relative to vehicle group. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT02078609 | Novartis Pharmaceuticals|Novartis |
AML and High Risk MDS
|
March 20, 2014 | Phase 1 |
| NCT02144038 | Novartis Pharmaceuticals|Novartis |
Relapsed and Refractory Multiple Myeloma
|
July 23, 2014 | Phase 1 |
| NCT02160951 | Novartis Pharmaceuticals|Novartis |
Multiple Myeloma
|
September 2014 | Phase 1 |
| NCT01456689 | Novartis Pharmaceuticals|Novartis |
Multiple Myeloma
|
April 25, 2012 | Phase 1 |
| NCT02370706 | Novartis Pharmaceuticals|Novartis |
Myelofibrosis
|
May 21, 2015 | Phase 1 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Solvent & Solubility
H 2 O : 50 mg/mL ( 97.39 mM ; Need ultrasonic)
DMSO : ≥ 46.7 mg/mL ( 90.97 mM )
* "≥" means soluble, but saturation unknown.
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 1.9479 mL | 9.7394 mL | 19.4787 mL |
| 5 mM | 0.3896 mL | 1.9479 mL | 3.8957 mL |
| 10 mM | 0.1948 mL | 0.9739 mL | 1.9479 mL |
-
1.
-
2.
Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline)
Solubility: ≥ 2.5 mg/mL (4.87 mM); Clear solution
References
- [1] Paíno T et al. The novel pan-PIM kinase inhibitor, PIM447, displays dual anti-myeloma and bone protective effects, and potently synergizes with current standards of care. Clin Cancer Res. 2016 Jul 20.
- [2] Burger MT et al. Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor
- [3] Peters TL et al. Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447. Oncotarget. 2016 Aug 20