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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C24H23F3N4O.HCl |
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分子量 | 476.92 | CAS No. | 1210608-43-7(freebase) | |
Solubility (25°C)* | 体外 | DMSO | 95 mg/mL (199.19 mM) | |
Ethanol | 95 mg/mL (199.19 mM) | |||
Water | Insoluble | |||
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
製品説明 | 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. |
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in vitro | 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]. |
in vivo | 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]. |
細胞アッセイ | 細胞株 | KG-1 cells |
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濃度 | 0.05, 0.5, and 5 μM | |
反応時間 | 2 h | |
実験の流れ | Following treatment of KG-1 cells with PIM447 for 2 h at the indicated concentrations, cells are lysed in RIPA buffer. Protein concentration is determined using a BCA assay, and 50 μg of lysate is separated by SDS-PAGE using 10% bis-Tris gels. Proteins are transferred onto 0.2 μm nitrocellulose membrane, and pS6RP/total S6RP are detected. Following incubation with secondary antibodies, antibody binding is detected using ECL Advance. |
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動物実験 | 動物モデル | KG-1 AML xenograft mouse model |
投薬量 | 30 or 100 mg/kg | |
投与方法 | oral administration |
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Data from [Data independently produced by , , Transl Oncol, 2018, 12(2):336-349]
PIM1 drives lipid droplet accumulation to promote proliferation and survival in prostate cancer [ Oncogene, 2024, 43(6):406-419] | PubMed: 38097734 |
Nuclear transport surveillance of p53 by nuclear pores in glioblastoma [ Cell Rep, 2023, S2211-1247(23)00893-8] | PubMed: 37552992 |
PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion [ J Cell Biol, 2023, 222(6)e202208136] | PubMed: 37042842 |
Defining the Role of PIM in Regulating Cytoskeletal Dynamics and Tumor Cell Invasion in Hypoxia [ The University of Arizona., 2023, ] | PubMed: None |
Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies [ Cancer Res, 2021, canres.1023.2021] | PubMed: 34625423 |
Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies [ Cancer Res, 2021, 81(23):6029-6043] | PubMed: 34625423 |
PIM447 inhibits oncogenesis and potentiates cisplatin effects in hepatoblastoma [ J Pediatr Surg, 2021, S0022-3468(21)00173-1] | PubMed: 33762119 |
2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors [ Chem Pharm Bull (Tokyo), 2021, 69(9):854-861] | PubMed: 34470949 |
Anti-platelet Properties of Pim Kinase Inhibition Is Mediated Through Disruption of Thromboxane A2 Receptor Signalling [ Haematologica, 2020, 28;haematol.2019.223529] | PubMed: 32467143 |
Measurement and models accounting for cell death capture hidden variation in compound response. [ Cell Death Dis, 2020, 20;11(4):255] | PubMed: 32312951 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
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