L-685,458

Biological Activity

L-685,458 is a potent and selective γ-secretase inhibitor (IC₅₀ = 17 nM) that displays > 50-fold selectivity over a range of aspartyl, serine and cysteine proteases. L-685,458 binds with high affinity to the related aspartyl protease, signal peptide peptidase (SPP; K_D = 5.1 nM), and inhibits SPP expressed in HEK293 cells (IC₅₀ = 10 μM). L-685,458 exhibits equal potency for inhibition of Aβ40 and Aβ42 peptides (IC₅₀ values are 48 and 67 nM respectively in human neuroblastoma cells). It also regulates CXCR4 and VEGFR2 expression through inhibition of Notch signaling in vitro.

Technical Data

The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis.
Tocris products are intended for laboratory research use only, unless stated otherwise.

Background References

1. ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA
   
   Oncogene, 2016;0(0):.
2. A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells
   P Saxena, BC Heng, P Bai, M Folcher, H Zulewski, M Fussenegge
   Nat Commun, 2016;7(0):11247.
3. Blood stem cell fate regulation by Delta-1-mediated rewiring of IL-6 paracrine signaling.
   Csaszar, Elizabet, Wang, Weijia, Usenko, Tatiana, Qiao, Wenlian, Delaney, Colleen, Bernstein, Irwin D, Zandstra, Peter W
   Blood, 2014;123(5):650-8.
4. Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes.
   Nakajima C, Kulik A, Frotscher M, Herz J, Schafer M, Bock H, May P
   J Biol Chem, 2013;288(30):21909-23.
5. Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes.
   Maury Y, Come J, Piskorowski R, Salah-Mohellibi N, Chevaleyre V, Peschanski M, Martinat C, Nedelec S
   Nat Biotechnol, 2015;33(1):89-96.
6. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid-β-protein precursor γ-secretase activity.
   Shearman et al.
   Biochemistry, 2000;39:8698
7. Up-regulation of the Notch ligand delta-like 4 inhibits VEGF-induced endothelial cell function.
   Williams et al.
   Blood, 2006;107:931
8. Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells.
   Williams CK, Segarra M, Sierra Mde L, Sainson RC, Tosato G, Harris AL
   Cancer Res., 2008-03-15;68(6):1889-95.

Product Datasheets