PF-04691502

PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with K_i of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 induces apoptosis. Phase 2.

CAS No. 1013101-36-4

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 33500	国内在庫あり
5mg	JPY 20200	国内在庫あり
50mg	JPY 96600	国内在庫あり

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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製品安全説明書

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PF-04691502関連製品

関連ターゲット	p110α p110β p110δ p110γ C2β Vps34	もっと見る
関連製品	LY294002 3-MA (3-Methyladenine) Dactolisib (BEZ235) Pictilisib (GDC-0941) Wortmannin Idelalisib (CAL-101) Buparlisib (BKM120) Alpelisib (BYL719) PI-103 TGX-221 ZSTK474 Omipalisib (GSK2126458) A66 Duvelisib (IPI-145) Copanlisib PIK-75 HCl IC-87114 740 Y-P (PDGFR 740Y-P) AS-605240 Taselisib (GDC 0032) SAR405 Apitolisib (GDC-0980) VPS34-IN1 PIK-90 AZD6482 Gedatolisib (PKI-587) HS-173 AS-252424 Eganelisib (IPI-549) VS-5584 (SB2343) GSK2636771 AZD8186 GSK1059615 Pilaralisib (XL147) TG100-115 CZC24832 Voxtalisib (XL765) XL147 analogue AS-604850 BGT226 (NVP-BGT226) maleate Quercetin Dihydrate VPS34 inhibitor 1 (Compound 19) Samotolisib (LY3023414) Voxtalisib (XL765) Analogue AMG319 umbralisib (TGR-1202) Nemiralisib Bimiralisib (PQR309) CH5132799 PKI-402 TG100713 Paxalisib (GDC-0084) SF2523 Serabelisib (TAK-117) GDC-0326 GNE-317 Inavolisib (GDC-0077) PIK-294 PI-3065 AZD8835 Seletalisib (UCB-5857) leniolisib (CDZ 173) (E)-Akt inhibitor-IV Gallein CAY10505 Selective PI3Kδ Inhibitor 1 (compound 7n) PF-4989216 GNE-477 GNE-493	もっと見る
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
human SKOV3 cells	Proliferation assay	3 days	Antiproliferative activity against human SKOV3 cells after 3 days by CellTiter-Glo assay, IC50=0.29 μM	25139570
human U87MG cells	Proliferation assay	4 days	Antiproliferative activity against human U87MG cells after 4 days by CellTiter-Glo assay, IC50=0.52 μM	25139570
human BT20 cells	Function assay		Inhibition of AKT phosphorylation at Ser 473 in human BT20 cells, IC50=0.013 μM	23506825
他の多くの細胞株試験データをご覧になる場合はこちらをクリックして下さい

生物活性

製品説明

PF-04691502 (PF4691502) is an ATP-competitive PI3K(α/β/δ/γ)/mTOR dual inhibitor with K_i of 1.8 nM/2.1 nM/1.6 nM/1.9 nM and 16 nM in cell-free assays, little activity against either Vps34, AKT, PDK1, p70S6K, MEK, ERK, p38, or JNK. PF-04691502 induces apoptosis. Phase 2.

Targets

PI3Kδ ^[1] (Cell-free assay)	PI3Kα ^[1] (Cell-free assay)	PI3Kγ ^[1] (Cell-free assay)	PI3Kβ ^[1] (Cell-free assay)	P-Akt (S473) ^[1] (Cell-free assay)	もっとクリックする
1.6 nM(Ki)	1.8 nM(Ki)	1.9 nM(Ki)	2.1 nM(Ki)	3.8 nM	もっとクリックする

In Vitro
In vitro	PF-04691502 potently inhibits recombinant class I PI3K and mTOR in biochemical assays and suppresses transformation of avian fibroblasts mediated by wild-type PI3K γ, δ, or mutant PI3Kα. In PIK3CA-mutant and PTEN-deleted cancer cell lines, PF-04691502 reduces phosphorylation of AKT T308 and AKT S473 (IC(50) of 7.5-47 nM and 3.8-20 nM, respectively) and inhibits cell proliferation (IC(50) of 179-313 nM). PF-04691502 inhibits mTORC1 activity in cells as measured by PI3K-independent nutrient stimulated assay, with an IC(50) of 32 nM and inhibits the activation of PI3K and mTOR downstream effectors including AKT, FKHRL1, PRAS40, p70S6K, 4EBP1, and S6RP. Short-term exposure to PF-04691502 predominantly inhibits PI3K, whereas mTOR inhibition persists for 24 to 48 hours. PF-04691502 induces cell cycle G(1) arrest, concomitant with upregulation of p27 Kip1 and reduction of Rb. ^[1]
Kinase Assay	Kinase Assay
Kinase Assay	The fluorescence polarization assay for ATP competitive inhibition is done as follows: mPI3Kα dilution solution (90 nM) is prepared in fresh assay buffer (50 mM Hepes pH 7.4, 150 mM NaCl, 5 mM DTT, 0.05% CHAPS) and kept on ice. The enzyme reaction contains 0.5 nM mouse PI3Kα (p110α/p85α complex purified from insect cells), 30 μM PIP2, PF-04691502 (0, 1, 4, and 8 nM), 5 mM MgCl₂, and 2-fold serial dilutions of ATP (0–800 μM). Final dimethyl sulfoxide is 2.5%. The reaction is initiated by the addition of ATP and terminated after 30 minutes with 10 mM EDTA. In a detection plate, 15 uL of detector/probe mixture containing 480 nM GST-Grp1PH domain and 12 nM TAMRA tagged fluorescent PIP3 in assay buffer is mixed with 15 uL of kinase reaction mixture. The plate is shaken for 3 minutes, and incubated for 35 to 40 minutes before reading on an LJL Analyst HT.
細胞実験	細胞株	BT20, U87MG, and SKOV3 cells
	濃度	0-3 mM
	反応時間	3 days
	実験の流れ	BT20, U87MG, and SKOV3 cells are plated at 3,000 cell/well in 96-well culture plates in growth medium with 10% FBS. Cells are incubated overnight and treated with DMSO (0.1% final) or serial diluted compound for 3 days. Resazurin is added to 0.1 mg/mL. Plates are incubated at 37 °C in 5% CO₂ for 3 hours. Fluorescence signals are read as emission at 590 nm after excitation at 530 nm. IC50 values are calculated by plotting fluorescence intensity to drug concentration in nonlinear curve
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	p-AKT / p-ERK p-S6 / S6		23826249
	Growth inhibition assay	Cell viability		28029662

In Vivo
In Vivo	Antitumor activity of PF-04691502 is observed in U87 (PTEN null), SKOV3 (PIK3CA mutation), and gefitinib- and erlotinib-resistant non-small cell lung carcinoma xenografts. ^[1] PF-04691502 inhibits tumor growth at 7 days by 72%. FDG-PET imaging revealed that PF-04691502 reduces glucose metabolism dramatically. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), are also dramatically inhibited following PF-04691502 treatment. ^[2]
動物実験	動物モデル	LSL-Kras^G12D heterozygous mice (B6.129-Kras^tm4Tyj) and Pten^del mice (c;129S4-Pten^tm1Hwu/J), Orthotopic transplant of ovarian tumors
	投与量	daily at either 7.5 or 10 mg/kg
	投与経路	Administered via oral gavage

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-01-11)
NCT01658176	Withdrawn	Breast Neoplasms	Pfizer	January 2013	Phase 2
NCT01420081	Terminated	Endometrial Neoplasms	Pfizer	January 19 2012	Phase 2
NCT01347866	Terminated	Advanced Cancer	Pfizer	October 2011	Phase 1

参考
[1] Yuan J, Mol Cancer Ther, 2011, 10(11), 2189-2199 [2] Kinross KM, Mol Cancer Ther, 2011, 10(8), 1440-1449 [3] Simmons BH, Cancer Chemother Pharmacol, 2012, 70(2), 213-220

参考

化学情報

分子量	425.48	化学式	C₂₂H₂₇N₅O₄
CAS No.	1013101-36-4	SDF	Download PF-04691502 SDFをダウンロードする
Smiles	CC1=C2C=C(C(=O)N(C2=NC(=N1)N)C3CCC(CC3)OCCO)C4=CN=C(C=C4)OC
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 : 14 mg/mL ( (32.9 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。)

Water : Insoluble

Ethanol : 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。

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):