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.

Product information

CAS Number: 292632-98-5

Molecular Weight: 672.85

Formula: C39H52N4O6

Synonym:

L-685

458

Chemical Name: tert-butyl N-[(2S, 3R, 5R)-5-benzyl-5-{[(1S)-1-{[(1S)-1-carbamoyl-2-phenylethyl]carbamoyl}-3-methylbutyl]carbamoyl}-3-hydroxy-1-phenylpentan-2-yl]carbamate

Smiles: CC(C)C[C@H](NC(=O)[C@@H](C[C@@H](O)[C@H](CC1=CC=CC=C1)NC(=O)OC(C)(C)C)CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(N)=O

InChiKey: MURCDOXDAHPNRQ-ZJKZPDEISA-N

InChi: InChI=1S/C39H52N4O6/c1-26(2)21-33(37(47)41-32(35(40)45)24-29-19-13-8-14-20-29)42-36(46)30(22-27-15-9-6-10-16-27)25-34(44)31(23-28-17-11-7-12-18-28)43-38(48)49-39(3,4)5/h6-20,26,30-34,44H,21-25H2,1-5H3,(H2,40,45)(H,41,47)(H,42,46)(H,43,48)/t30-,31+,32+,33+,34-/m1/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO : 83.3 mg/mL (123.80 mM; Need ultrasonic and warming)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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. L-685458 (5-40 μM; 24 hours) leads to a dramatic downregulation of Hes-1 in 786-O cells. 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.

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.

References:

1. Shearman, M.S., Beher, D., Clarke, E.E., Lewis, H.D., Harrison, T., Hunt, P.,
2. Guanghui Yang, et al. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell. 2021 Jan 21;184(2):521-533.e14.
3. Jonas Sjölund, et al. Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo. J Clin Invest. 2008 Jan;118(1):217-28.

Products are for research use only. Not for human use.