Home JAK/STAT Pim inhibitor PIM447 (LGH447) Hydrochloride

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PIM447 (LGH447) Hydrochloride Pim inhibitor

Cat.No.S7985

PIM447 (LGH447) Hydrochloride 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.
PIM447 (LGH447) Hydrochloride Pim inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 476.92

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Quality Control

Batch: Purity: 99.06%
99.06

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MOLM16 Antiproliferative assay 3 days Antiproliferative activity against human MOLM16 cells after 3 days by CellTiter-Glo assay, GI50=0.01μM 26505898
KG1 Antiproliferative assay 3 days Antiproliferative activity against human KG1 cells after 3 days by CellTiter-Glo assay, GI50=0.01μM 26505898
EOL-1 Antiproliferative assay 3 days Antiproliferative activity against human EOL-1 cells after 3 days by CellTiter-Glo assay, GI50=0.01μM 26505898
M07e Antiproliferative assay 3 days Antiproliferative activity against human M07e cells after 3 days by CellTiter-Glo assay, GI50=0.05μM 26505898
UKE1 Antiproliferative assay 3 days Antiproliferative activity against human UKE1 cells after 3 days by CellTiter-Glo assay, GI50=0.09μM 26505898
MV411 Antiproliferative assay 3 days Antiproliferative activity against human MV411 cells after 3 days by CellTiter-Glo assay, GI50=0.13μM 26505898
KMS11 Antiproliferative assay 72 hrs Antiproliferative activity against luciferase expressing human KMS11 cells after 72 hrs by Cell-TiterGlo assay, EC50=0.17μM 26505898
KMS11 Function assay 1 hr Inhibition of PIM kinase in luciferase expressing human KMS11 cells assessed as inhibition of phosphorylation of S6RP after 1 hr by electrochemiluminescence assay, EC50=0.18μM 26505898
CMK Antiproliferative assay 3 days Antiproliferative activity against human CMK cells after 3 days by CellTiter-Glo assay, GI50=0.28μM 26505898
KG1 Function assay 100 mg/kg 24 hrs Unbound plasma concentration in mouse xenografted with human KG1 cells at 100 mg/kg, po after 24 hrs by LC/MS/MS analysis, Cp(f)=0.3μM 26505898
SET2 Antiproliferative assay 3 days Antiproliferative activity against human SET2 cells after 3 days by CellTiter-Glo assay, GI50=0.48μM 26505898
CMK-11-5 Antiproliferative assay 3 days Antiproliferative activity against human CMK-11-5 cells after 3 days by CellTiter-Glo assay, GI50=1.03μM 26505898
MOLM13 Antiproliferative assay 3 days Antiproliferative activity against human MOLM13 cells after 3 days by CellTiter-Glo assay, GI50=1.39μM 26505898
HEL 92.1.7 Antiproliferative assay 3 days Antiproliferative activity against human HEL 92.1.7 cells after 3 days by CellTiter-Glo assay, GI50=1.66μM 26505898
TF1 Antiproliferative assay 3 days Antiproliferative activity against human TF1 cells after 3 days by CellTiter-Glo assay, GI50=1.96μM 26505898
MUTZ8 Antiproliferative assay 3 days Antiproliferative activity against human MUTZ8 cells after 3 days by CellTiter-Glo assay, GI50=1.99μM 26505898
OCI-M1 Antiproliferative assay 3 days Antiproliferative activity against human OCI-M1 cells after 3 days by CellTiter-Glo assay, GI50=2.57μM 26505898
SKM1 Antiproliferative assay 3 days Antiproliferative activity against human SKM1 cells after 3 days by CellTiter-Glo assay, GI50=2.69μM 26505898
OCI-AML3 Antiproliferative assay 3 days Antiproliferative activity against human OCI-AML3 cells after 3 days by CellTiter-Glo assay, GI50=2.92μM 26505898
P31/FUJ Antiproliferative assay 3 days Antiproliferative activity against human P31/FUJ cells after 3 days by CellTiter-Glo assay, GI50=5.06μM 26505898
MONO-MAC-1 Antiproliferative assay 3 days Antiproliferative activity against human MONO-MAC-1 cells after 3 days by CellTiter-Glo assay, GI50=5.19μM 26505898
THP1 Antiproliferative assay 3 days Antiproliferative activity against human THP1 cells after 3 days by CellTiter-Glo assay, GI50=5.31μM 26505898
OCI-AML2 Antiproliferative assay 3 days Antiproliferative activity against human OCI-AML2 cells after 3 days by CellTiter-Glo assay, GI50=5.53μM 26505898
NB4 Antiproliferative assay 3 days Antiproliferative activity against human NB4 cells after 3 days by CellTiter-Glo assay, GI50=7μM 26505898
PL21 Antiproliferative assay 3 days Antiproliferative activity against human PL21 cells after 3 days by CellTiter-Glo assay, GI50=8.56μM 26505898
SIG-M5 Antiproliferative assay 3 days Antiproliferative activity against human SIG-M5 cells after 3 days by CellTiter-Glo assay, GI50=8.66μM 26505898
NOMO1 Antiproliferative assay 3 days Antiproliferative activity against human NOMO1 cells after 3 days by CellTiter-Glo assay, GI50=10μM 26505898
F-36P Antiproliferative assay 3 days Antiproliferative activity against human F-36P cells after 3 days by CellTiter-Glo assay, GI50=10μM 26505898
OCI-AML5 Antiproliferative assay 3 days Antiproliferative activity against human OCI-AML5 cells after 3 days by CellTiter-Glo assay, GI50=10μM 26505898
KG1 Antitumor assay 30 mg/kg 11 days Antitumor activity against human KG1 cells xenografted in mouse assessed as tumor stasis at 30 mg/kg, po qd measured after 11 days post tumor implantation 26505898
KG1 Antitumor assay 30 to 100 mg/kg 11 days Antitumor activity against human KG1 cells xenografted in mouse assessed as tumor regression at 30 to 100 mg/kg, po qd measured after 11 days post tumor implantation in presence of 100 mg/kg Ara-C 26505898
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Solubility

In vitro
Batch:

DMSO : 95 mg/mL (199.19 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 95 mg/mL

Water : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight
Dilution Calculator Molecular Weight Calculator

In vivo
Batch:

In vivo Formulation Calculator (Clear solution)

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Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
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Chemical Information, Storage & Stability

Molecular Weight 476.92 Formula

C24H23F3N4O.HCl

 Storage (From the date of receipt)
CAS No. 1210416-52-6 -- Storage of Stock Solutions

Synonyms N/A Smiles CC1CC(CC(C1)N)C2=C(C=NC=C2)NC(=O)C3=NC(=C(C=C3)F)C4=C(C=CC=C4F)F

Mechanism of Action

Targets/IC50/Ki
Pim1
(Cell-free assay)
6 pM(Ki)
Pim3
(Cell-free assay)
9 pM(Ki)
Pim2
(Cell-free assay)
18 pM(Ki)
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

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02160951 Completed
Multiple Myeloma
Novartis Pharmaceuticals|Novartis
 September 2014 Phase 1
NCT02078609 Completed
AML and High Risk MDS
Novartis Pharmaceuticals|Novartis
 March 20 2014 Phase 1
NCT01456689 Completed
Multiple Myeloma
Novartis Pharmaceuticals|Novartis
 April 25 2012 Phase 1

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