PIM447 DIHYDROCHLORIDE
中文名称:
PIM447 DIHYDROCHLORIDE
中文同义词:
泛PIM抑制剂
英文名称:
N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide
英文同义词:
PIM-447 (dihydrochloride);LGH-447 dihydrochloride;EOS-62253;PIM-447 2HCl
CAS号:
1820565-69-2
分子式:
C24H23F3N4O
分子量:
440.4608296
EINECS号:
相关类别:
细胞生物学试剂
Mol文件:
1820565-69-2.mol
生物活性
PIM447 dihydrochloride (LGH447 dihydrochloride) 是一种有效的、口服的、选择性的泛 PIM 激酶抑制剂，对 PIM1、PIM2 和 PIM3 的 Ki 值分别为 6、18 和 9 pM。PIM447 dihydrochloride 具有双重抗肿瘤和骨保护作用。PIM447 dihydrochloride 诱导细胞凋亡。
体外研究
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).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.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.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.
Cell Viability Assay
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
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
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
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.
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).
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.
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 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.
体内研究
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.
Animal Model: RPMI-8226-luc cells are injected intravenously into 6-week-old female NODSCID-IL-2Rγ -/- (NSG) mice
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.
Animal Model:
RPMI-8226-luc cells are injected intravenously into 6-week-old female NODSCID-IL-2Rγ -/- (NSG) mice
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.
