[CAS NO. 1210608-43-7] PIM447 (LGH447)
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PRODUCTS SPECIFICATIONS [1210608-43-7]
Catalog
SLK-S7985
Brand
Selleck
CAS
1210608-43-7
DESCRIPTION [1210608-43-7]
Overview
| MDL | MFCD30489724 |
|---|---|
| Molecular Weight | 476.92 |
| Molecular Formula | C24H23F3N4O.HCl |
| SMILES | O=C(NC1=C([C@H]2C[C@@H](N)C[C@@H](C)C2)C=CN=C1)C3=NC(C4=C(F)C=CC=C4F)=C(F)C=C3 |
For research use only.
Storage
3 years,-20°C,powder
1 years,-80°C,in solvent
1 years,-80°C,in solvent
Shipping
Room temperature shipping(Stability testing shows this product can be shipped without any cooling measures.)
Preparing Stock Solutions
| 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 |
| 50 mM | 0.0419 mL | 0.2097 mL | 0.4194 mL |
Description
PIM447 (LGH447) is a novel 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 (>10-fold differential relative to the Ki on PIMs). PIM447 induces .
Targets
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. 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.
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.
References
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