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In HeLa and SiHa cells, L-685,458 (8 μM) blocked Notch activation. In L-685,458-treated cells, Hes1 nuclear translocation was largely blocked and about 6.63% of HeLa and 9.03% of SiHa cells were subjected to apoptosis. L-685,458 (10 μM, 3 days) inhibited Notch pathways and caused accumulation of oocytes at the pachytene stages and decreased the number of oocytes that are able to reach diplotene. In SGHPL-5 cells, L-685,458 suppressed canonical notch activity. L-685,458 significantly increased the amount of BrdU-labeled primary CTB cells. L-685,458 increased migration of SGHPL-5 cells. L-685,458 (10 μM, 48 hours) strongly increased motility of the nonproliferating EVTs. L-685,458 (0.5 μM) attenuated the isoflurane-induced increase in Tau-PS262 levels in WT mice and AD Tg mice primary neurons. |
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L-685,458 is a selective and Potent inhibitor of γ-secretase with IC50 value of 17 nM[1].
γ-Secretase 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 Aβfrom the amyloid precusor protein.? γ-Secretase has been considered as an important drug target for Alzheimer's disease. γ-Secertase also is responsible for Notch processing which is related to cancer such as leukemia.
L-685,458 is a transition state analogue inhibitor.
It is a pan-inhibitor of γ-secretase which decrease the products of Aβ(42) and Aβ(40) peptides. It displays a selectivity of 50-fold or greater inhibition than a range of aspartyl, serine, and cysteine protease in vitro membrane assay. L-685,458 reduced the product both total Aβand Aβ42 in human primary neuronal cells with IC50 value of 115 nM for Aβand Aβ42 for 200 nM[2]. L-685,458 also inhibitedγ-secretase activity by characterizing the production of total secreted Aβ?by ELISA with IC50 value of about 5 nM in HEK 293 cells overexpressing human APP751.
L-685,458 reduced the cortical total Aβwith a 50% reduction occurring at 100 mg/kg in a dose-dependent manner in PDAPP, and similar reductions in cortical Aβ42 were observed. L-685,458 decreased brain levels of Aβwhen given orally to Tg2576 mice that are transgenic for human APPV717F mutation. [3] L-685,458 also inhibit the Notch signaling, then affects embryonic development in zebrafish embryos[4].
References:
1.Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL: L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry 2000, 39(30):8698-8704.
2.Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ et al: Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001, 76(1):173-181.
3.Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B, Merchant KM: The gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces A beta levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther 2003, 305(3):864-871.
4.Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C: A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 2002, 3(7):688-694. |
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