PIM447 (LGH447)
目录号 : GC25743PIM447 (LGH447) is a novel pan-PIM kinase inhibitor with Ki values of 6 pM, 18 pM, 9 pM for PIM1, PIM2, PIM3 respectively. It also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). PIM447 induces apoptosis.
Cas No.:1210608-43-7(freebase)
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PIM447 (LGH447) is a novel pan-PIM kinase inhibitor with Ki values of 6 pM, 18 pM, 9 pM for PIM1, PIM2, PIM3 respectively. It also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). PIM447 induces apoptosis.
The kinase selectivity of PIM447 is first determined in biochemical assays for a panel of 68 diverse protein kinases that included PIM2 as well as 9 lipid kinases. In this panel, only PIM2 is significantly inhibited by PIM447 with an IC50 of <0.003 μM, the lowest sensitivity range for the assay. PIM447 also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). The biochemical IC50 for all other kinases tested in this panel is >9 μM. In follow-up cellular assays of GSK3β inhibition, PIM447 is tested up to 20 μM and is not active[1]. 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 mTORC1 pathway. PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization[2].
Low to moderate in vivo CL is observed for PIM447 across species, as CL values of 20, 28, and 8 mL/min/kg are observed in mouse, rat, and dog, respectively. The volume of distribution is consistently large across species, with Vss of 5.3, 6.4, and 3.6 L/kg observed in mouse, rat, and dog, respectively. Additionally, PIM447 exhibits high oral bioavailability across species, as 84%, 70%, and 71% is observed in mouse, rat, and dog, respectively. The stability of PIM447 in human plasma is high, >90% after a 3 h incubation, and the human plasma protein binding of PIM447 is 95%. With the combination of potent in vitro activity and low to moderate CL, PIM447 demonstrates in vivo target modulation (pS6RP), single agent antitumor activity in a KG-1 AML mouse xenograft model, and druglike properties suitable for development[1]. PIM447 significantly reduces the tumor burden and prevents tumor-associated bone loss in a disseminated murine model of human myeloma[2].
[1] Burger MT, et al. J Med Chem. 2015, 58(21):8373-86. [2] PaÍno T, et al. Clin Cancer Res. 2017, 23(1):225-238.
| Cas No. | 1210608-43-7(freebase) | SDF | Download SDF |
| 分子式 | C24H23F3N4O.HCl | 分子量 | 476.92 |
| 溶解度 | DMSO: 88 mg/mL (184.52 mM);Water: Insoluble;Ethanol: 88 mg/mL (184.52 mM) | 储存条件 | Store at -20°C |
| General tips | 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 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PIM Kinases in Multiple Myeloma
Cancers (Basel) 2021 Aug 26;13(17):4304.PMID:34503111DOI:PMC8428354
Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.