Description
LY411575 is a potent γ-secretase inhibitor with IC50 value of 0.078 nM and 0.082 nM for membrane and cell-based, respectively.
Product Overview
LY-411575 is a potent inhibitor of γ-secretase with IC50 value of 0.078 nM in membrane assay. γ-Secertase is one of intramenbrane-cleaving aspartyl protease which cleaves many type-I membrane proteins and many of them have important biological functions. γ-Secretase is a multi-subunit protease and it contains presenilin, nicastrin, APH-1(Anterior Pharynx-defective 1) and PEN-2.Presenilin contains Asp258 and Asp385 embedded in the sixth and seventh transmembrane domain and forms the active site. The feature of being a membrane integrated protease complex makes it difficult to be purified as well as studying its mechanism. γ-secretase is responsible for the generation Aβ from the amyloid precursor protein. γ-Secertase has been considered as an important drug target for Alzheimers disease. γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia. LY-411,575 significantly inhibits theγ-secretase activity in vitro. LY-411,575 inhibits the production of Aβ production with IC50 value of 0.078 nM in membrane-assay and 0.082 nM in cell-basedγ-secretase assays, respectively. LY-411,575 also affects the Notch pathway by inhibiting Notch S3 cleavage with IC50 value of 0.39 nM. LY-411,575 treatment also significantly inhibited the Notch pathway by inhibiting the γ-secretase activity luciferase activity in primary KS cells. LY-411,575 also induced the apoptosis though Notch pathway inhibition in primary and immortalized Kaposis sarcoma (KS) tumor cells. LY-411,575 decreases the levels of brain and plasma Aβ 40 and-42 at 10 mg/kg oral doses. LY-411,575 also decreases cortical Aβ 40 levels in transgenic CRND8 mice with ED50 ≈ 0.6 mg/kg. LY-411,575 also induced significantly intestinal goblet cell hyperplasia and thymus atrophy by inhibiting Notch signaling pathway at higher doses in vivo.
Targets
γ-secretase; Notch S3 cleavage
IC50
0.078 nM (membrane-based) 0.082 nM (cell-based); 0.39 nM
Molecular Formula
C26H23F2N3O4
Chemical Name
(2S)-2-[[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide
Solubility
Soluble in DMSO > 10 mM
Shipping Conditions
Evaluation sample solution: ship with blue ice. All other available size: ship with RT, or blue ice upon request
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