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PIM447 (LGH447) Hydrochloride

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化学構造

CAS No. 1210416-52-6

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 67000 国内在庫あり
JPY 29500 国内在庫あり
JPY 55500 国内在庫あり

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製品安全説明書

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PIM447 (LGH447) Hydrochloride関連製品

シグナル伝達経路

Pim Signaling Pathways

Pimシグナル伝達経路

Pim阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
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
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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生物活性

製品説明 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.
Targets
Pim1 [1]
(Cell-free assay)		 Pim3 [1]
(Cell-free assay)		 Pim2 [1]
(Cell-free assay)
6 pM(Ki) 9 pM(Ki) 18 pM(Ki)
In Vitro
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].
細胞実験 細胞株 KG-1 cells
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.
In Vivo
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].
動物実験 動物モデル KG-1 AML xenograft mouse model 
投与量 30 or 100 mg/kg
投与経路 oral administration
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

化学情報

分子量 476.92 化学式

C24H23F3N4O.HCl
CAS No. 1210416-52-6 SDF --
Smiles CC1CC(CC(C1)N)C2=C(C=NC=C2)NC(=O)C3=NC(=C(C=C3)F)C4=C(C=CC=C4F)F
保管

In vitro
Batch:

DMSO : 95 mg/mL ( (199.19 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 95 mg/mL

Water : Insoluble

モル濃度計算器

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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Handling Instructions

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