Gedatolisib (PKI-587)

別名：PF-05212384

製品コード：S2628 純度：99.09%

Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM in cell-free assays, respectively. Phase 2.

CAS No. 1197160-78-3

サイズ	価格(税別)	在庫状況
5mg	JPY 25500	国内在庫あり
50mg	JPY 100500	国内在庫あり
1g	JPY 598500	国内在庫なし(納期7~10日)

代表番号: 045-509-1970\|電子メール：[email protected] よく尋ねられる質問

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現在のバッチを見る：純度： 99.09%

99.09

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関連化合物ライブラリー	Kinase Inhibitor Library PI3K/Akt Inhibitor Library Apoptosis Compound Library Cell Cycle compound library NF-κB Signaling Compound Library	もっと見る

シグナル伝達経路

PI3Kシグナル伝達経路

PI3K阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Incubation Time	活性情報	PMID
SF9 insect cells	Function assay	2 h	Inhibition of human PI3Kalpha expressed in SF9 insect cells after 2 hrs by fluorescence polarization assay, IC50=0.0004 μM	21763134
SF9 insect cells	Function assay	2 h	Inhibition of human PI3Kgamma expressed in SF9 insect cells after 2 hrs by fluorescence polarization assay, IC50=0.011μM	21763134
MDA-MB-361 cells	Growth inhibition assay	72 h	Growth inhibition of human MDA-MB-361 cells after 72 hrs, IC50=0.003 μM	21763134
human PC3 cells	Growth inhibition assay	72 h	Growth inhibition of human PC3 cells after 72 hrs, IC50=0.011 μM	21763134
MDA-MB-361 cells	Cytotoxicity assay		Cytotoxicity against human MDA-MB-361 cells, IC50=0.004 μM	20166697
PC3MM2 cells	Cytotoxicity assay		Cytotoxicity against human PC3MM2 cells, IC50=0.0131 μM	20166697
MDA-MB-361 cells	Function assay		Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.008 μM	20166697
MDA-MB-361 cells	Function assay		Inhibition of Akt S473 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.01 μM	20166697
MDA-MB-361 cells	Function assay		Inhibition of eNOS phosphorylation in human MDA-MB-361 cells by Western blotting	20166697
MDA-MB-361 cells	Function assay		Inhibition of PARS40 phosphorylation in human MDA-MB-361 cells by Western blotting	20166697
MDA-MB-361 cells	Function assay		Inhibition of GSK3 kinase phosphorylation in human MDA-MB-361 cells by Western blotting	20166697
MDA-MB-361 cells	Function assay		Inhibition of mTOR TORC1 kinase activity in human MDA-MB-361 cells assessed as suppression of p70S6K phosphorylation at < 30 nM	20166697
MDA-MB-361 cells	Function assay		Inhibition of mTOR TORC1 kinase activity in human MDA-MB-361 cells assessed as suppression of 4EBP1 phosphorylation at < 30 nM	20166697
MDA-MB-361 cells	Function assay		Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells xenografted mouse model upto 36 hrs	20166697
MDA-MB-361 cells	Function assay		Inhibition of Akt S473 phosphorylation in human MDA-MB-361 cells xenografted mouse model upto 36 hrs	20166697
MDA-MB-361 cells	Function assay		Induction of PARP cleavage in human MDA-MB-361 cells xenografted mouse model upto 18 hrs	20166697
MDA-MB-361 cells	Function assay		Antitumor activity against human MDA-MB-361 cells xenografted mouse model assessed as reduction in tumor volume at 20 mg/kg, iv on day 1, 5, 9	20166697
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生物活性

製品説明

Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM in cell-free assays, respectively. Phase 2.

Targets

PI3Kα ^[1] (Cell-free assay)	mTOR ^[1] (Cell-free assay)	PI3Kγ ^[1] (Cell-free assay)
0.4 nM	1.6 nM	5.4 nM

In Vitro
In vitro	PKI-587 shows potent inhibitory activity against PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. Furthermore, PKI-587 also exhibits its potency against the most frequently occurring mutant forms of PI3Kα, notably the H1047R and E545K with IC50 of 0.6 nM and 0.6 nM, respectively. ^[1] Correlated with suppression of phosphorylation of PI3K/mTOR signaling pathway proteins, PKI-587 causes tumor cell growth inhibition in MDA-361 and PC3-MM2 cell lines with IC50 of 4 nM and 13.1 nM, respectively. ^[1]
Kinase Assay	PI3K and mTOR kinase assay
Kinase Assay	Enzyme assays are done in fluorescent polarization (FP) format, adapted from the Echelon K-1100 PI3K FP assay kit protocol. Human class I PI3Ks and PI3K-α mutants (E545K and H1047R) are produced in Sf9 or purchased from Upstate Biotech. GST-GRP1 (murine) is produced in Escherichia coli and isolated by GST-Sepharose. Assay buffers are reaction buffer [20 mM HEPES (pH 7.1), 2 mM MgCl₂, 0.05% CHAPS, and 0.01% β-mercaptoethanol] and stop/detection buffer [100 mM HEPES (pH 7.5), 4 mM EDTA, 0.05% CHAPS]. FP reaction is run for 30 minutes at room temperature in 20 μL of reaction buffer containing 20 μM phosphatidylinositol 4,5-bisphosphate (PIP2), 25 μM ATP, and <4% DMSO. FP reaction is stopped with 20 μL of stop/detection buffer (10 nM probe and 40 nM GST-GRP), and after 2 hours, data are collected using an Envision plate reader. The routine assays with purified FLAG-TOR (FL and 3.5) are performed in 96-well plates as follows. Enzymes are first diluted in kinase assay buffer (10 mM Hepes (pH 7.4), 50 mM NaCl, 50 mM β-glycerophosphate, 10 mM MnCl₂, 0.5 mM DTT, 0.25 μM microcystin LR, and 100 μg/mL BSA). To each well, 12 μL of the diluted enzyme is mixed briefly with 0.5 μL test inhibitor or control vehicle dimethyl sulfoxide (DMSO). The kinase reaction is initiated by adding 12.5 μL kinase assay buffer containing ATP and His6-S6K to give a final reaction volume of 25 μL containing 800 ng/mL FLAG-TOR, 100 μM ATP, and 1.25 μM His6-S6K. The reaction plate is incubated for 2 hours (linear at 1–6 hours) at room temperature with gentle shaking and then terminated by adding 25 μL Stop buffer (20 mM Hepes (pH 7.4), 20 mM EDTA, and 20 mM EGTA).
細胞実験	細胞株	MDA-361 and PC3-MM2
	濃度	0-10 μM
	反応時間	72 hours
	実験の流れ	Cells are plated in 96-well culture plates at about 3000 cells per well. One day following plating, PKI-587 is added to cells. Three days after PKI-587 treatment, viable cell densities are determined by measuring metabolic conversion (by viable cells) of the dye MTS, a previously established cell proliferation assay. For each assay, MTS and PMS stocks are freshly thawed and mixed (MTS/PMS, 20:1). The MTS/PMS mixture is then added to 96-well cell plates at 20 μL/well, and plates are incubated for 1 hour–2 hours in cell culture incubator. MTS assay results are read in a 96-well format plate reader by measuring absorbance at 490 nm. The effect of each PKI-587 treatment is calculated as a percentage of control cell growth obtained from vehicle-treated cells grown in the same culture plate.
実験結果図	Methods	Biomarkers	結果図	PMID
	Growth inhibition assay	Cell viability		29978469
	Western blot	p-AKT / p-mTOR / p-p70S6K / p-S6K / p-4E-BP1 / AKT / mTOR / p70S6K / S6K / 4EBP1 TSC1 / TSC2 / Raptor		29978469

In Vivo
In Vivo	In nude mice, PKI-587 treatment at 25 mg/kg iv leads to low plasma clearance (7 (mL/min)/kg), high volume of distribution (7.2 L/kg), and long half-life, (14.4 hours). In the MDA-361 xenograft model, PKI-587 produces potent antitumor efficacy with the minimum efficacious dose (MED) of 3 mg/kg against MDA-361 tumors and maximum tolerated single dose (MTD) of 30 mg/kg. While in the H1975 (non-small-cell lung carcinoma, mutant EGFR [L858R, T790M]) xenograft model, PKI-587 at 25 mg/kg for 7 weeks results in 90% survival of the group treated. ^[1]
動物実験	動物モデル	MDA-361 and H1975 cells are injected subcutaneously into the nude mice.
	投与量	≤30 mg/kg
	投与経路	Administered via i.v.

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT02438761	Terminated	Therapy-related Acute Myeloid Leukemia and Myelodysplastic Syndrome\|Acute Myeloid Leukemia in Relapse\|de Novo Acute Myeloid Leukemia at Diagnostic	Institut Curie\|Fondation ARC\|National Cancer Institute France	August 31 2015	Phase 2
NCT02069158	Completed	Breast Cancer\|NSCLC\|Ovary Cancer\|Endometrial Cancer\|Small Cell Lung Cancer (SCLC)\|Head and Neck (HNSCC)	Cristiana Sessa\|Oncology Institute of Southern Switzerland	April 2014	Phase 1
NCT01420081	Terminated	Endometrial Neoplasms	Pfizer	January 19 2012	Phase 2

参考
[1] Venkatesan AM, et al. J Med Chem. 2010, 53(6), 2636-2645. [2] Gedaly R, et al. J Surg Res. 2011, doi.org/10.1016/j.jss.2011.10.045.

参考

化学情報

分子量	615.73	化学式	C₃₂H₄₁N₉O₄
CAS No.	1197160-78-3	SDF	Download Gedatolisib (PKI-587) SDFをダウンロードする
Smiles	CN(C)C1CCN(CC1)C(=O)C2=CC=C(C=C2)NC(=O)NC3=CC=C(C=C3)C4=NC(=NC(=N4)N5CCOCC5)N6CCOCC6
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1个月-20°Cin solvent

In vitro
Batch:

DMSO : 3 mg/mL ( (4.87 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 : 1 mg/mL

Water : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

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）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

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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