Synergistic inhibition of Aβ production by combinations of γ-secretase modulators.

Autor: Robertson AS; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Iben LG; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Wei C; Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Meredith JE Jr; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Drexler DM; Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Banks M; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Vite GD; Lead Discovery and Lead Profiling, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Olson RE; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Thompson LA; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Albright CF; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Ahlijanian MK; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA., Toyn JH; Neuroscience Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06437, USA. Electronic address: jeremy.toyn@yale.edu.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2017 Oct 05; Vol. 812, pp. 104-112. Date of Electronic Publication: 2017 Jul 08.
DOI: 10.1016/j.ejphar.2017.07.019
Abstrakt: Alzheimer's disease is associated with the accumulation of amyloid-β (Aβ) in the brain. In particular, the 42-amino acid form, Aβ1-42, is thought to play a key role in the disease. It is therefore of interest that diverse compounds, known as γ-secretase modulators (GSM), can selectively decrease Aβ1-42 production without inhibiting the production of other forms of Aβ. Here we describe the novel discovery of synergistic inhibition of Aβ by certain combinations of GSMs. Cell cultures were treated with pairwise combinations of GSMs to determine how Aβ peptide production was affected. Analysis of isobolograms and calculation of the combination index showed that BMS-869780 and GSM-2 were highly synergistic. Additional combinations of GSMs revealed that inhibition of Aβ occurred only when one GSM was of the "acid GSM" structural class and the other was of the "non-acid GSM" class. A total of 15 representative acid/non-acid GSM combinations were shown to inhibit Aβ production, whereas 10 pairwise combinations containing two acid GSMs or containing two non-acid GSMs did not inhibit Aβ. We also discovered that lasalocid, a natural product, is a potent GSM. Lasalocid is unique in that it did not synergize with other GSMs. Synergism did not translate in vivo perhaps because of biochemical differences between the cell culture model and brain. These findings reinforce the pharmacological differences between different structural classes of GSMs, and may help to exploit the potential of γ-secretase as a drug target.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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