Compound E

γ-Secretase is a multimeric aspartyl protease that regulates signaling pathways by proteolytically cleaving substrates, abrogating or releasing signaling molecules.¹ Two well-known substrates are the carboxyl-terminal fragments (CTFs) of the receptor Notch, which has key roles in development, and that of amyloid precursor protein (APP), which is important in Alzheimer’s disease.¹ Compound E is a potent, cell-permeable, and selective inhibitor of γ-secretase, blocking the cleavage of both APP and Notch CTFs with IC₅₀ values of ~0.3 nM.^2,3,4 Compound E induces neuronal differentiation, impairs ovarian folliculogenesis, and suppresses thymocyte development by preventing Notch activation by γ-secretase.^5,6,7

1.Jurisch-Yaksi, N., Sannerud, R., and Annaert, W.A fast growing spectrum of biological functions of γ-secretase in development and diseaseBiochim. Biophys. Acta1828(12)2815-2827(2013) 2.Seiffert, D., Bradley, J.D., Rominger, C.M., et al.Presenilin-1 and -2 are molecular targets for γ-secretase inhibitorsJ. Biol. Chem.275(44)34086-34091(2000) 3.Beher, D., Wrigley, J.D.J., Nadin, A., et al.Pharmacological knock-down of the presenilin 1 heterodimer by a novel g -secretase inhibitor. Implications for presenilin biologyJ. Biol. Chem.276(48)45394-45402(2001) 4.Zhao, G., Mao, G., Tan, J., et al.Identification of a new presenilin-dependent ζ-cleavage site within the transmembrane domain of amyloid precursor proteinJ. Biol. Chem.279(49)50647-50650(2004) 5.Ferrari-Toninelli, G., Bonini, S.A., Uberti, D., et al.Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cellsNeuro. Oncol.12(12)1231-1243(2010) 6.Jovanovic, V.P., Sauer, C.M., Shawber, C.J., et al.Intraovarian regulation of gonadotropin-dependent folliculogenesis depends on notch receptor signaling pathways not involving Delta-like ligand 4 (Dll4)Reprod. Biol. Endocrinol.1143(2013) 7.Doerfler, P., Shearman, M.S., and Perlmutter, R.M.Presenilin-dependent γ-secretase activity modulates thymocyte developmentProc. Natl. Acad. Sci. USA98(16)9312-9317(2001)