LY411575

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.^1,2 LY411575 can induce apoptosis in Kaposi’s sarcoma cells as well as promote intestinal goblet cell differentiation in a mouse model of colitis.^2,3 It has also been observed to promote neural differentiation of mouse embryonic stem cells.⁴

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1. Czirr, E., Leuchtenberger, S., Dorner-Ciossek, C., et al. Insensitivity to Aβ42-lowering nonsteroidal anti-inflammatory drugs and γ-secretase inhibitors is common among aggressive presenilin-1 mutations. The Journal of Biological Chemisty 282(34), 24504-24513 (2007).

2. Curry, C.L., Reed, L.L., Golde, T.E., et al. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi’s sarcoma tumor cells. Oncogene 24(42), 6333-6344 (2005).

3. Okamoto, R., Tsuchiya, K., Nemoto, Y., et al. Requirement of Notch activation during regeneration of the intestinal epithelia. Am. J. Physiol. Gastrointest. Liver Physiol. 296(1), G23-G35 (2009).

4. Abranches, E., Silva, M., Pradier, L., et al. Neural differentiation of embryonic stem cells in vitro: A road map to neurogenesis in the embryo. PLoS One 4(7), e6286 (2009).