(1S,3R,5R)-PIM447 dihydrochloride a potent PIM inhibitor extracted with IC50 values of 0.095 μM for Pim1, 0.522 μM for Pim2 and 0.369 μM for Pim3. It is the isomer of PIM447 (also known as LGH447) which is a novel and potent pan-PIM (proviral insertion site of Moloney murine leukemia) 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 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 is currently undergoing several clinical trials.
理化性质和储存条件
| Molecular Weight (MW) | 513.39 |
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| Formula | C24H25Cl2F3N4O |
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| CAS No. | 1210608-43-7 (free base); 1210416-52-6 (HCl); 1820565-69-2 (2HCl) |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 88 mg/mL (184.5 mM) |
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| Water: <1 mg/mL |
| Ethanol: 88 mg/mL (184.5 mM) |
| SMILES Code | 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.[H]Cl.[H]Cl |
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| Synonyms | (1S,3R,5R)-PIM447 dihydrochloride; (1S,3R,5R)-PIM-447; (1S,3R,5R)-PIM 447; (1S,3R,5R)-LGH-447 dihydrochloride; (1S,3R,5R)-LGH 447; (1S,3R,5R)-LGH447 |
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实验参考方法
| In Vitro | In vitro activity: 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 1='' 5='' the='' lowest='' sensitivity='' range='' for='' assay.='' pim447='' also='' inhibits='' and='' but='' at='' a='' significantly='' lower='' potency='' with='' ic50='' between='' m=''>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. 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.
Kinase Assay: PIM447 (also known as LGH447) is a novel and potent pan-PIM (proviral insertion site of Moloney murine leukemia) 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).
Cell Assay: 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. 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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| 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. PIM447 significantly reduces the tumor burden and prevents tumor-associated bone loss in a disseminated murine model of human myeloma. |
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| Animal model | KG-1 AML xenograft mouse model |
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| Formulation & Dosage | 50 mM acetate buffer, pH 4; 30 or 100 mg/kg; p.o. |
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| References | J Med Chem. 2015 Nov 12;58(21):8373-86; Clin Cancer Res. 2017 Jan 1;23(1):225-238. |
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