上海金畔生物科技有限公司为生命科学和医药研发人员提供生物活性分子抑制剂、激动剂、特异性抑制剂、化合物库、重组蛋白,专注于信号通路和疾病研究领域。
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。
生物活性 |
PIM447 dihydrochloride (LGH447 dihydrochloride) is a potent, orally available, and selective pan-PIM kinase inhibitor, with Ki 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].
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IC50 & Target |
Ki: 6 pM (PIM1); 18 pM (PIM1); 9 pM (PIM3)[1]
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体外研究 (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 IC50 values 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 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].
上海金畔生物科技有限公司 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. |
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体内研究 (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].
上海金畔生物科技有限公司 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. |
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Clinical Trial |
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分子量 |
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Formula |
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CAS 号 |
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运输条件 |
Room temperature in continental US; may vary elsewhere.
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储存方式 |
4°C, sealed storage, away from moisture
*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
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溶解性数据 |
In Vitro:
H2O : 50 mg/mL (97.39 mM; Need ultrasonic)
DMSO : ≥ 46.7 mg/mL (90.97 mM)
* “≥” means soluble, but saturation unknown.
配制储备液
浓度 溶剂体积 质量 |
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 |
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)。-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液,再依次添加助溶剂:
——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用; 以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶
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参考文献 |
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[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 in Clinical Trials for Hematological Malignancies. J Med Chem. 2015 Nov 12;58(21):8373-86.
[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
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