Name: Crenigacestat (LY3039478)
Brand: Selleck Chemicals
SKU: S7169
Availability: InStock
Rating: 5 (25 reviews)

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Quality Control

Batch: Purity: 99.89%

99.89

Related Targets	JAK TGF-beta/Smad Wnt/beta-catenin ERK GSK-3 ROCK Hedgehog/Smoothened PKA Secretase STAT
Other Notch Inhibitors	FLI-06 IMR-1 RIN1 (RBPJ Inhibitor-1) Limantrafin (CB-103) NVS-ZP7-4 Jagged-1 (188-204) (TFA) IMR-1A

Cell Culture, Treatment & Working Concentration

Cell Lines	Assay Type	Incubation Time	Activity Description	PMID
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
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
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
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
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
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
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
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
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
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
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
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
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 93 mg/mL (200.24 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 93 mg/mL

Water : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
Mass value Mass unit	Concentration value Concentration unit	Volume value Volume unit	Molecular weight (g/mol)

Dilution Calculator Molecular Weight Calculator

In vivo batch selection In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validated by Selleck labs. Should you need adjustments to this formulation, contact our sales team for custom testing.	9.500mg/ml (20.45mM)	Taking the 1 mL working solution as an example, add 50 μL of 190 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg

Average weight of animals: g

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Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Chemical Information, Storage & Stability

Molecular Weight	464.44	Formula	C₂₂H₂₃F₃N₄O₄	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	1421438-81-4	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent

Mechanism of Action

Targets/IC₅₀/Ki	Notch ~1 nM
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.
References	[1] http://www.rsc.org/images/Warren_Porter_tcm18-237088.pdf [2] http://cancerres.aacrjournals.org/content/73/8_Supplement/1131.short [3] https://pubmed.ncbi.nlm.nih.gov/27909050/ [4] https://pubmed.ncbi.nlm.nih.gov/27103434/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
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

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Crenigacestat (LY3039478) Notch/γ-Secretase Inhibitor

Chemical Structure

Molecular Weight: 464.44