Home Stem Cells & Wnt Notch inhibitor - Gamma-secretase inhibitor Crenigacestat (LY3039478) For research use only.

Crenigacestat (LY3039478)

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

Crenigacestat (LY3039478) Chemical Structure

Crenigacestat (LY3039478) Chemical Structure

CAS No. 1421438-81-4

Purity & Quality Control

Crenigacestat (LY3039478) Related Products

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation 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
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Biological Activity

Description 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].
Cell Research Cell lines K07074 cells
Concentrations 100 nM
Incubation Time 24, 48, 72, 96 h
Method

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].
Animal Research Animal Models Mice
Dosages 8 mg/kg
Administration oral gavage
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

Chemical Information & Solubility

Molecular Weight 464.44 Formula

C22H23F3N4O4
CAS No. 1421438-81-4 SDF Download Crenigacestat (LY3039478) SDF
Smiles CC(C(=O)NC1C2=CC=CC=C2C3=C(N=CC=C3)N(C1=O)CCO)NC(=O)CCC(F)(F)F
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 93 mg/mL ( (200.24 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 93 mg/mL

Water : Insoluble


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In vivo
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Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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