209984-57-6

γ-Secretase is a multi-subunit aspartyl protease that regulates signaling pathways by proteolytically cleaving substrates, abrogating or releasing signaling molecules. One well-known substrate of this enzyme is Notch, a transmembrane receptor that plays a key role in cell fate decisions including cell proliferation, differentiation, and apoptosis. LY411575 is a cell-permeable γ-secretase inhibitor (IC₅₀ = 0.14 nM) that has been shown to block Notch activation in vitro at 500 μM. LY411575 can induce apoptosis in Kaposi’s sarcoma cells as well as promote intestinal goblet cell differentiation in a mouse model of colitis. It has also been observed to promote neural differentiation of mouse embryonic stem cells.

ChEBI: A dibenzoazepine that is 5,7-dihydro-6H-dibenzo[b,d]azepin-6-one which is substituted at the 7 pro-S position by the C-terminal carboxamide nitrogen of N /element>2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyacetyl]-L-alaninamide. It is a potent, cell permeable and selective gamma-secretase inhibitor. It has been tested as a possible treatment for Alzheimer's disease and shows promise for its potential to counteract severe hearing loss.

LY-411575 is potent, cell permeable and selective γ-secretase inhibitor that reduces Aβ/42 after acute or chronic treatment, and blocks Notch activation. Studies (Cancer Cell) have shown that treatment with LSN-411575 arrests KrasG12V-driven NSCLCs in association with inhibition of HES1 expression and ERK phosphorylation.

γ-secretase

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[1] EVA CZIRR. Insensitivity to Abeta42-lowering nonsteroidal anti-inflammatory drugs and gamma-secretase inhibitors is common among aggressive presenilin-1 mutations.[J]. The Journal of Biological Chemistry, 2007, 282 34: 24504-24513. DOI: 10.1074/jbc.m700618200
[2] CHRISTINE L CURRY. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi”s sarcoma tumor cells[J]. Oncogene, 2005, 24 42: 6333-6344. DOI: 10.1038/sj.onc.1208783
[3] RYUICHI OKAMOTO. Requirement of Notch activation during regeneration of the intestinal epithelia.[J]. American journal of physiology. Gastrointestinal and liver physiology, 2009, 296 1: G23-35. DOI: 10.1152/ajpgi.90225.2008
[4] ELSA ABRANCHES. Neural differentiation of embryonic stem cells in vitro: a road map to neurogenesis in the embryo.[J]. PLoS ONE, 2009: e6286. DOI: 10.1371/journal.pone.0006286