BMS-754807

製品コード：S1124 純度：99.72%

BMS-754807 is a potent and reversible inhibitor of IGF-1R/InsR with IC50 of 1.8 nM/1.7 nM in cell-free assays, less potent to Met (c-Met), Aurora A/B, TrkA/B and Ron, and shows little activity to Flt3, Lck, MK2, PKA, PKC etc. Phase 2.

CAS No. 1001350-96-4

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 40500	国内在庫あり
5mg	JPY 27000	国内在庫あり
10mg	JPY 40500	国内在庫あり
50mg	JPY 115500	国内在庫あり
1g	JPY 748500	国内在庫なし(納期7~10日)

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BMS-754807関連製品

関連ターゲット	Insulin Receptor	もっと見る
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関連化合物ライブラリー	Kinase Inhibitor Library Tyrosine Kinase Inhibitor Library PI3K/Akt Inhibitor Library Cell Cycle compound library Angiogenesis Related compound Library	もっと見る

シグナル伝達経路

IGF-1Rシグナル伝達経路

IGF-1R阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Concentration	活性情報	PMID
M109	Growth inhibitory assay	~5 μM	IC50=1.055 μM	19996272
HCT116	Growth inhibitory assay	~5 μM	IC50=0.852 μM	19996272
DU4475 2.431	Growth inhibitory assay	~5 μM	IC50=2.431 μM	19996272
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

特性

Muti-inhibitor of the IGR-1R/IR family.

Targets

Insulin Receptor ^[1] (Cell-free assay)	IGF-1R ^[1] (Cell-free assay)	TrkB ^[1] (Cell-free assay)	Met ^[1] (Cell-free assay)	TrkA ^[1] (Cell-free assay)	もっとクリックする
1.7 nM	1.8 nM	4.1 nM	5.6 nM	7.4 nM	もっとクリックする

In Vitro
In vitro	BMS-754807 effectively inhibits the growth of a broad range of human tumor cell lines of different histologic origins including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, and gastric), and hematopoietic (multiple myeloma and leukemia), the IC50 values range from 5 nM to 365 nM for the most sensitive cell lines. BMS-754807 inhibits proliferation of IGF-1R-Sal cells and RH41 cells with IC50 of 7 nM and 5 nM. BMS-754807 inhibits phosphorylation of IGF-1R in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 13 nM, 6 nM and 21 nM. BMS-754807 inhibits phosphorylation of Akt in IGF-1R-Sal cells, Rh41 and Geo with IC50 of 22 nM, 13 nM and 16 nM. BMS-754807 induces greater apoptosis in Rh41 cells by 24 hours as indicated by an increased sub-G1 peak (23.1%), compared with control (2.4%). ^[1] BMS-754807 inhibits the phosphorylation of IGF-1R (IC50 = 13nM) and the downstream targets Akt (IC50 = 22nM) and MAPK (IC50 = 13nM) in the IGF-Sal cell line with IC50 consistent with the antiproliferative IC50 (7 nM) in this cell line. The crystal structure of BMS-754807 cocrystallized with the kinase domain of IGF-1R shows that the donor/acceptor/donor hydrogen bond triad with Met1052 and Glu1050 within the hinge region of the kinase. ^[2] BMS-754807 shows a median EC50 value of 0.62 μM against 23 cell lines in the pediatric preclinical testing program (PPTP). ^[3]
Kinase Assay	Kinase inhibition assays
Kinase Assay	The primary screen for BMS-754807 is an in vitro kinase assay using recombinant human IGF-1 receptor enzyme in biochemical assays using synthetic peptide KKSRGDYMTMQIG as a phosphoacceptor substrate. The selectivity profile is evaluated against multiple recombinant enzymes that are generated at BMS or purchased externally. The enzymatic assays are performed in Ubottom 384-well plates using a 30 μL reaction volume in assay buffer (100 mM Hepes pH 7.4, 10 mM MgCl₂, 0.015% Brij35 and 4 mM DTT). The 60 minute reactions are initiated by combining ATP (concentration equivalent to K_m ATP), 1.5 μM labeled peptide substrate, enzyme and BMS-754807. The reactions are terminated with EDTA. The reaction mixtures are analyzed on the Caliper LabChip 3000 by electrophoretic separation of the fluorescent substrate and phosphorylated product. Inhibition data are calculated by comparison to enzyme-free control reactions for 100% inhibition and vehicle-only reactions for 0% inhibition. Compounds are dissolved in DMSO, 10mM stock and evaluated at eleven concentrations. IC50 values are derived by non-linear regression analysis of the dose response curves.
細胞実験	細胞株	IGF-1R-Sal, RH41 and Geo cell lines
	濃度	365 nM
	反応時間	72 hours
	実験の流れ	Cells are grown at their optimal density in RPMI +GlutaMax supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cell proliferation is evaluated by incorporation of ³H-thymidine into DNA after exposure of cells to BMS-754807 for 72 hours. Results are expressed as an IC50, which is the drug concentration required to inhibit cell proliferation by 50% compared with untreated control cells.
実験結果図	Methods	Biomarkers	結果図	PMID
	Growth inhibition assay	Cell viability		30754629
	Western blot	p-IGFIRRβ/InsRβ / IGFIRβ / p-AKT / AKT / p-ERK / ERK		26136493

In Vivo
In Vivo	BMS-754807 (12.5mg/kg, orally) inhibits IGF-1R phosphorylation in tumor and serum in IGF-1R-Sal tumor–bearing nude mice. BMS-754807 inhibits tumor growth in a selected group of epithelial (IGF-1R-Sal, GEO, and Colo205), hematopoietic (JJN3), and mesenchymal (RD1 and Rh41) xenograft tumor models with TGI ranging from 53% to 115%. ^[1] BMS-754807 (6.25 mg/kg) achieves complete tumor growth inhibition in the transgenic-derived IGF-Sal tumor mouse model with correlated inhibition of pIGF-1R and pAKT. The protein binding for BMS-754807 ranges from of 98.5% in mouse plasma to 95.9% in human plasma. BMS-754807 results in clearance of 113 (mL/min)/kg, 20 (mL/min)/kg, 3.5 (mL/min)/kg and 41 (mL/min)/kg. ^[2] BMS-754807 (25 mg/kg) significantly inhibits tumor in KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 xenografts mice model. ^[3]
動物実験	動物モデル	IGF-1R-Sal, GEO, Colo205, JJN3, RD1 or Rh41 tumor–bearing nude mice
	投与量	150 mg/kg
	投与経路	Orally

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT01525823	Completed	Healthy Volunteers	Bristol-Myers Squibb	February 2012	Phase 1
NCT00908024	Terminated	Colorectal Cancer\|Head and Neck Cancer\|Neoplasm Metastasis	Bristol-Myers Squibb	October 2009	Phase 1\|Phase 2
NCT00898716	Completed	Neoplasms	Bristol-Myers Squibb	September 2009	Phase 1
NCT00788333	Completed	Breast Cancer	Bristol-Myers Squibb	July 2009	Phase 1\|Phase 2

参考
[1] Carboni JM, et al. Mol Cancer Ther, 2009, 8(12), 3341-3349. [2] Wittman MD, et al. J Med Chem, 2009, 52(23), 7360-7363. [3] Kolb EA, et al. Pediatr Blood Cancer, 2011, 56(4), 595-603.

参考

化学情報

分子量	461.49	化学式	C₂₃H₂₄FN₉O
CAS No.	1001350-96-4	SDF	Download BMS-754807 SDFをダウンロードする
Smiles	CC1(CCCN1C2=NN3C=CC=C3C(=N2)NC4=NNC(=C4)C5CC5)C(=O)NC6=CN=C(C=C6)F
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ケ月-20°Cin solvent

In vitro
Batch:

DMSO : 92 mg/mL ( (199.35 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 : 92 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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