L-685458 serves as a potent γ-secretase inhibitor (GSI), classified as a transition state analog (TSA), and effectively inhibits amyloid β-protein precursor γ-secretase activity with an IC50 of 17 nM, displaying more than 50-100-fold selectivity against other tested aspartyl proteases. This compound impedes γ-secretase-mediated cleavage of APP-C99 and Notch-100 with IC50 values of 301.3 nM and 351.3 nM, respectively, and is investigated for its potential in Alzheimer’s disease (AD) and cancer research[1].[2].
体内研究
When administered percutaneously at a dose of 5 mg/kg for two weeks, L-685458 shows antitumor activity in mouse hepatoma models. It specifically reduces EpCAM production, excluding necrotic areas, and diminishes HES1 staining in the nucleus[4].
体外研究
The compound is shown to decrease the formation of both Aβ(40) and Aβ(42) peptides in various cell lines, exhibiting IC50 values of 402 nM, 113 nM, and 48 nM against Neuro2A h AβPP695, CHO h AβPP695, and SHSY5 spβA4CTF for Aβ(40) reduction, respectively. For Aβ(42) reduction, the IC50 values are 775 nM, 248 nM, and 67 nM, respectively[1].
L-685458, at concentrations ranging from 5 to 40 μM over a 24-hour period, significantly reduces Hes-1 levels in 786-O cells[3].
This inhibitor also demonstrates effectiveness against various hepatoma cell lines, including Huh7, HepG2, HLE, and SKHep1, with IC50 values of 12.91 μM, 12.69 μM, 21.76 μM, and 12.18 μM, respectively[4].
作用机制
L-685458 is an aspartyl protease transition state mimic which exhibits stereoselectivity to AβPP γ-secretase activity with much less potency to aspartyl, serine, and cysteine protease activity, thereby abolishing the formation of all Aβ peptide species.[1]
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