Crenigacestat (LY3039478)

製品コードS7169 バッチS716904

化学情報

	Synonyms		Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₂H₂₃F₃N₄O₄
	分子量	464.44	CAS No.	1421438-81-4
Solubility (25°C)*	体外	DMSO	93 mg/mL (200.24 mM)
		Ethanol	93 mg/mL (200.24 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Crenigacestat (LY3039478) は、経口のNotchおよびガンマセクレターゼ阻害剤であり、Notchに対するIC50は0.41 nMです。
in vitro	Crenigacestat (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. It also potently inhibits mutant Notch receptor activity. Treatment with this gamma secretase inhibitor significantly inhibited the growth of 2 CCRCC (Clear cell renal cell carcinoma) cell lines in a concentration dependent manner. It 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. Furthermore, it led to G0/G1 cell cycle arrest in CCRCC cells.
in vivo	Crenigacestat (LY3039478) exhibits an oral bioavailability (%F) of 65% in mice, with a clearance (CL) of 41 mL/min/kg and a VDss of 3.8 L/kg. In rats, its oral bioavailability is 65%, CL is 98 mL/min/kg, and VDss is 4.9 L/kg, while in dogs, oral bioavailability reaches 67%, with CL at 3.8 mL/min/kg and VDss at 1.4 L/kg. In a xenograft tumor model, this compound 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. In immunodeficient NSG mice xenografted with 769-P CCRCC cells, it significantly increased survival and delayed tumor growth in independent cohorts, demonstrating in vivo efficacy in CCRCC.

プロトコル(参考用のみ)

細胞アッセイ	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 Crenigacestat (LY3039478) on K07074 cell growth, this compound 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.
動物実験	動物モデル	Mice
	投薬量	8 mg/kg
	投与方法	oral gavage

参考

http://www.rsc.org/images/Warren_Porter_tcm18-237088.pdf
http://cancerres.aacrjournals.org/content/73/8_Supplement/1131.short
https://pubmed.ncbi.nlm.nih.gov/27909050/

https://pubmed.ncbi.nlm.nih.gov/27103434/

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カスタマーフィードバック

: Data from [Data independently produced by , , Eur Rev Med Pharmacol Sci, 2018, 22(13):4121-4127]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Immunosuppressive JAG2+ tumor-associated neutrophils hamper PD-1 blockade response in ovarian cancer by mediating the differentiation of effector regulatory T cells [ Cancer Commun (Lond), 2025, 10.1002/cac2.70021]	PubMed: 40120139
Targeting cancer-associated fibroblasts/tumor cells cross-talk inhibits intrahepatic cholangiocarcinoma progression via cell-cycle arrest [ J Exp Clin Cancer Res, 2024, 43(1):286]	PubMed: 39415286
Tolerable glycometabolic stress boosts cancer cell resilience through altered N-glycosylation and Notch signaling activation [ Cell Death Dis, 2024, 15(1):53]	PubMed: 38225221
Cellular senescence primes liver fibrosis regression through Notch-EZH2 [ MedComm (2020), 2023, 4(5):e346]	PubMed: 37614965
Cellular senescence primes liver fibrosis regression through Notch-EZH2 [ MedComm -2020), 2023, 4(5):e346]	PubMed: 37614965
Loss of p53 enhances the tumor-initiating potential and drug resistance of clonogenic multiple myeloma cells [ Blood Adv, 2023, 7(14):3551-3560]	PubMed: 37042949
Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling [ Stem Cell Reports, 2023, 18(7):1516-1533]	PubMed: 37352850
Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer [ bioRxiv, 2023, 2023.01.11.523584]	PubMed: 36711890
Notch-triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through eNOS [ Hepatology, 2022, 10.1002/hep.32332]	PubMed: 35006626
CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype [ J Exp Clin Cancer Res, 2022, 41(1):65]	PubMed: 35172861

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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