Crenigacestat (LY3039478)

製品コード：S7169 純度：99.89%

Crenigacestat (LY3039478) is an oral Notch and gamma-secretase inhibitor with IC50 of 0.41 nM for Notch.

CAS No. 1421438-81-4

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 38800	国内在庫あり
5mg	JPY 25500	国内在庫あり
25mg	JPY 85500	国内在庫あり
1g	JPY 1050000	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

文献中Selleckの製品使用例（24）

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製品安全説明書

現在のバッチを見る：純度： 99.89%

99.89

Crenigacestat (LY3039478)関連製品

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関連化合物ライブラリー	Kinase Inhibitor Library FDA-approved Drug Library Stem Cell Signaling Compound Library GPCR Compound Library Stem Cell Differentiation Compound Library	もっと見る

Notch阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Incubation Time	活性情報	PMID
MOLT-4	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MOLT-4 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00074 μM.	24900678
HCT 116	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human HCT 116 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00072 μM.	24900678
MIAPaCa2	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MIAPaCa2 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00071 μM.	24900678
MOLT-3	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MOLT-3 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00061 μM.	24900678
MDA-MB-231	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MDA-MB-231 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.0005 μM.	24900678
A375	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A375 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00048 μM.	24900678
BxPC3	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human BxPC3 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00039 μM.	24900678
U-87-MG	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human U-87-MG cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00028 μM.	24900678
HEL 92.1.7	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human HEL 92.1.7 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00023 μM.	24900678
SW480	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human SW480 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.0001 μM.	24900678
K562	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human K562 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00074 μM.	24900678
CCRF-CEM	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human CCRF-CEM cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00076 μM.	24900678
DLD1	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human DLD1 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00098 μM.	24900678
A2780	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A2780 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00103 μM.	24900678
SUP-T1	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human SUP-T1 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00124 μM.	24900678
Jurkat	Function assay	24 hrs	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human Jurkat cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50 = 0.00595 μM.	24900678
HEK293deltaE12	Function assay		Inhibition of gamma-secretase mediated cleavage of transfected mouse Notch 1 (1703-2183) harboring N-terminal 23 aminoacid signal peptide sequence in human HEK293deltaE12 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after, IC50 = 0.00041 μM.	24900678
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生物活性

製品説明

Crenigacestat (LY3039478) is an oral Notch and gamma-secretase inhibitor with IC50 of 0.41 nM for Notch.

Targets

Notch ^[1]

~1 nM

In Vitro
In vitro	LY3039478 is a novel small molecule that is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with an IC50 of ∼1nM in most of the tumor cell lines tested. LY3039478 also potently inhibits mutant Notch receptor activity^[2]. Treatment with a gamma secretase inhibitor, LY3039478, significantly inhibited the growth of 2 CCRCC(Clear cell renal cell carcinoma) cell lines in a concentration dependent manner. LY3039478 treatment also led to decreased expression of Myc and Cyclin A1, two genes that were part of the NOTCH driven proliferative signature in murine and human model systems. LY3039478 treatment also led to G0/G1 cell cycle arrest in CCRCC cells^[3].
細胞実験	細胞株	K07074 cells
	濃度	100 nM
	反応時間	24, 48, 72, 96 h
	実験の流れ	K07074 cells were plated to 24-well plates at 10⁵ cell/well. Viability of cells was assessed in quadruplicates at indicated timepoints using the CellTiter-Glo luminescent cell viability assay. To study the effect of the small molecular compounds on K07074 cell growth the compounds or DMSO were added to the growth media 24 h after seeding. The cells were incubated with inhibitors and DMSO as indicated. Cell viability was assessed as described above. Each experiment was carried out in triplicate and at least 3 independent experiments were performed.

In Vivo
In Vivo	In mice, its oral bioavalability(%F) is 65%, clearance(CL)=41 mL/min/kg, VDss = 3.8 L/kg. In Rats, its oral bioavalability(%F) is 65%, CL=98 mL/min/kg, VDss=4.9 L/kg. In Dogs, its oral bioavalability (%F) is 67%, CL=3.8 mL/min/kg, VDss=1.4 L/kg^[1]. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. The inhibition of Notch cleavage also resulted in the induction of apoptosis in a Notch-dependent xenograft model^[2]. In immunodeficient NSG mice xenografted with 769-P CCRCC cells, LY3039478 treatment resulted in significantly increased survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC^[3].
動物実験	動物モデル	Mice
	投与量	8 mg/kg
	投与経路	oral gavage

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT02906618	Completed	Healthy	Eli Lilly and Company	October 4 2016	Phase 1
NCT02917733	Completed	Healthy	Eli Lilly and Company	September 2016	Phase 1
NCT02836600	Completed	Advanced Solid Tumor	Eli Lilly and Company	September 9 2016	Phase 1
NCT02518113	Completed	T-cell Acute Lymphoblastic Leukemia\|T-cell Lymphoblastic Lymphoma	Eli Lilly and Company	October 1 2015	Phase 1\|Phase 2

参考
[1] Eli Lilly Company. The 8th SCI-RSC Symposium on Proteinase Inhibitor Design. 2013. [2] Mark H. Bender, et al. Cancer Res, 2013, 73(8 Suppl):Abstract nr 1131. [3] Bhagat TD, et al. J Biol Chem. 2017, 292(3):837-846. [4] Mäemets-Allas K, et al. Biochem Biophys Res Commun. 2016, 474(1):118-25. + 展開

参考

[4] Mäemets-Allas K, et al. Biochem Biophys Res Commun. 2016, 474(1):118-25.

+ 展開

化学情報

分子量	464.44	化学式	C₂₂H₂₃F₃N₄O₄
CAS No.	1421438-81-4	SDF	Download Crenigacestat (LY3039478) SDFをダウンロードする
Smiles	CC(C(=O)NC1C2=CC=CC=C2C3=C(N=CC=C3)N(C1=O)CCO)NC(=O)CCC(F)(F)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 : 93 mg/mL ( (200.24 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 : 93 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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