L-685458

L-685458 is a potent transition state analog (TSA) γ-secretase inhibitor (GSI). L-685458 inhibits amyloid β-protein precursor γ-secretase activity with IC₅₀ of 17 nM, shows greater than 50-100-fold selectivity over other aspartyl proteases tested. L685458 inhibits γ-secretase-mediated cleavage of APP-C99 and Notch-100 with IC₅₀s of 301.3 nM and 351.3 nM, respectively. L-685458 can be used for the research of alzheimer’s disease (AD) and cancers^[1][2]. In Vitro: L-685458 reduces both Aβ(40) and Aβ(42) peptide formation in 3 different cells. It against Neuro2A h AβPP695, CHO h AβPP695, and SHSY5 spβA4CTF reduction of Aβ(40) with IC₅₀ values of 402 nM, 113 nM and 48 nM, respectively. And the IC₅₀ values are 775 nM, 248 nM, 67 nM, respectively^[1].
L-685458 (5-40 μM; 24 hours) leads to a dramatic downregulation of Hes-1 in 786-O cells^[3].
L-685458 has inhibitory effects in hepatoma cell lines, it against Huh7, HepG2, HLE and SKHep1 cells with IC₅₀ of 12.91 μM, 12.69 μM, 21.76 μM and 12.18 μM, respectively^[4].
In Vivo: L-685458 (percutaneous administration; 5 mg/kg; 2 weeks) has antitumor effects in mouse hepatoma models. L-685458 inhibits EpCAM production except in necrotic areas. And HES1 staining is also diminished in the nucleus^[4].