Crenigacestat

SKU: orb1303976

Description

Crenigacestat (LY3039478) is a potent, orally bioavailable small molecule inhibitor of Notch signaling, demonstrating an IC50 of ~1 nM in various tumor cell lines. It effectively suppresses mutant Notch receptor activity and, in xenograft models, reduces Notch target gene expression and N1ICD cleavage within tumors. This inhibitor is a valuable research tool for studying Notch pathway roles in cancer and other diseases in both in vitro and in vivo settings.

Research Area

Neuroscience, Protein Biochemistry, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 1421438-81-4
• MW: 464.44
• Purity: 98.14%
• Formula: C₂₂H₂₃F₃N₄O₄
• SMILES: C[C@H](NC(=O)CCC(F)(F)F)C(=O)N[C@H]1c2ccccc2-c2cccnc2N(CCO)C1=O
• Target: Gamma-secretase
• Solubility: DMSO:150 mg/mL (322.97 mM);H2O:< 1 mg/mL (insoluble or slightly soluble);10% DMSO+40% PEG300+5% Tween 80+45% Saline:2 mg/mL (4.31 mM)

Bioactivity

• Target IC50:
  Notch1:1 nM
• 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. In a xenograft tumor model, Crenigacestat 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, Crenigacestat treatment resulted in significantly increased survival and delayed tumor growth in independent cohorts of mice demonstrating in vivo efficacy in CCRCC.
• In Vitro:
  Crenigacestat is a novel small molecule that is an exquisitely potent inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with an IC50 of ～1 nM in most of the tumor cell lines tested. Crenigacestat also potently inhibits mutant Notch receptor activity. Treatment with a gamma secretase inhibitor, Crenigacestat, significantly inhibited the growth of 2 CCRCC(Clear cell renal cell carcinoma) cell lines in a concentration dependent manner. Crenigacestat 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. Crenigacestat treatment also led to G0/G1 cell cycle arrest in CCRCC cells.
• Cell Research:
  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. (Only for Reference)

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Gamma secretase, Gammasecretase, LY3039478, LY-3039478, LY 3039478, liver, Notch-1, Notch, inhibit, Inhibitor, CCRCC, Crenigacestat, γ-secretase

Compound Identifiers

PubChem CID

71236992