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]
L-685458 细胞实验
Cell Line
Concentration
Treated Time
Description
References
CHO 7W cells
7.5 µM
24 h
To inhibit the catalytic activity of γ-secretase
Nat Commun. 2010 Nov 30;1:130.
SKOV3 cells
0.5 and 2 μM
To investigate the inhibitory effect of L-685458 on γ-secretase activity, results showed that L-685458 significantly blocked the production of p80Her2.
Cancer Sci. 2020 Dec;111(12):4417-4428.
Primary neurons of AppSwe mice
1 µM
12 h
To investigate if NHE6 inhibition or knockdown alters BACE1 activity, results showed that NHE6 inhibition or knockdown did not alter BACE1 activity, and the amount of β-CTF remained unchanged.
Elife. 2021 Oct 7;10:e72034.
Inner ear stem cells
1 μg/ml
5 days
Inhibition of γ-secretase increased the differentiation of inner ear stem cells into hair cells, as evidenced by increased immunostaining for myosin VIIa and Math1.
J Neurosci. 2011 Jun 8;31(23):8351-8.
hiMPs
660 ng/ml
24 h
Block NOTCH signaling pathway, restore myogenic differentiation potential of hiMPs
EMBO Mol Med. 2022 Oct 10;14(10):e14526.
SH-SY5Y cells
1 µM
Inhibited APL1b secretion and induced intracellular accumulation of APLP1 C-terminal fragment (CTF) stubs
EMBO Mol Med. 2009 Jul;1(4):223-35.
cortical neurons
1 µM
1 hour
To study the effect of the γ-secretase inhibitor L-685458 on the nuclear localization of NRG1-ICD, results showed that L-685458 could block B4-ECD-induced nuclear localization of NRG1-ICD.
J Neurosci. 2010 Jul 7;30(27):9199-208.
Hippocampal neurons
1 µM
24 h
Inhibited γ-secretase activity, increased mEPSC frequency and amplitude
J Neurosci. 2011 Aug 24;31(34):12083-93.
Cortical neurons
1–10 µM
24 h
Inhibited γ-secretase activity, significantly increased N-cadherin CTF1 fragment levels
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