Avagacestat (BMS-708163)

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Biological Activity

Description	Avagacestat (BMS-708163) is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch. Phase 2.
Targets	Aβ40	Aβ42
IC50	0.3 nM	0.27 nM [1]
In vitro	BMS-708163 exhibits weaker selectivity for inhibition of Notch processing with 193-fold IC50 value. [1]
In vivo	Oral administration of BMS-708163 significantly reduces Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs. BMS-708163 has no dose-limiting effects in dogs (3 mg/kg during 6 months), with a high brain to plasma ratio (2.4). [1]
Features	Appears to be more “notch sparing” than semagacestat (LY450139).

Protocol(Only for Reference)

Kinase Assay: ^[1]

Inhibition of Aβ formation

BMS-708163 is assayed for Aβ40 or Aβ42 inhibition in cells using H4 APP751 SWE clone 8.20, an H4 neuroglioma cell line stably expressing the Swedish mutant of APP751. Cells are maintained in log phase through twice weekly passage at a 1:20 dilution. For IC50 determinations, 30 μL cells (1.5×104 cells/well) in DMEM media containing 0.0125% BSA are seeded directly into 384-well plates containing 0.1 μL serially diluted BMS-708163 in DMSO. Following incubation for 19 hours in 5% CO2 at 37 °C, plates are briefly centrifuged (103rpm, 5 min). A 10 μL aliquot from each well is transferred to a second assay plate for Aβ40 measurements. Antibody cocktails are freshly prepared by dilution into 40 mM Tris-HCl (pH 7.4) with 0.2% BSA and added to assay plates. For Aβ42 measurements, antibodies specific for the Aβ42 neoepitope (565, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and the N-terminal sequence of Aβ peptide (26D6, developed at SIBIA/Bristol-Myers Squibb; conjugated to APC) are mixed and 20 μL of the mixture is added to each well of the incubated cell plate yielding a final concentration of 0.8 ng/well 565 and 75 ng/well 26D6. For the Aβ40 measurements, antibodies specific for the Aβ40 neoepitope (TSD, developed at Bristol-Myers Squibb; conjugated to the Wallac reagent) and 26D6 as described above are mixed and 20 μL of the mixture is added to the 10 μL aliquots which have been removed previously from the cell plate yielding a final concentration of 1.6 ng/well TSD and 17.5 ng/well 26D6. Assay plates containing antibodies are sealed with aluminum foil and incubated overnight at 4 °C. Signal is determined using a Viewlux counter and IC50 values are determined.

Animal Study: ^[1]

Animal Models	Female Harlan Sprague-Dawley rats or ATM-405-142K9 with 7- 10 month old Na?ve, grade II beagles
Dosages	10 mg/kg (rats) or 2.5 mg/kg (dogs)
Administration	Dosed daily by oral gavage

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00890890	Active, not recruiting	Alzheimer’s Disease	Bristol-Myers Squibb	2009-05	Phase 2

Chemical Information

Download Avagacestat (BMS-708163) SDF

Chemical Name	(2R)-2-(N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chlorophenylsulfonamido)-5,5,5-trifluoropentanamide

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.52088	5.2088	10.4176	15.6264

Customer Reviews (2)

Click to enlarge	Rating
	Source	Stem Cells. 2014 Jan;32(1):301-12 . Avagacestat (BMS-708163) purchased from Selleck
	Method	CellTiter-Blue assay
	Cell Lines	GICs
	Concentrations	0.1-10 uM
	Incubation Time	72 h
	Results	γ Secretase inhibitor BMS-708163 effectively showed dose-dependent growth inhibition of GICs. panel of GICS lines was treated with various concentrations of γ secretase inhibitor BMS-708163. Cells were treated with increasing concentrations of γ secretase inhibitor in triplicate wells for 72 hours, and cell viability was assessed by CellTiter-Blue assay as described in Materials and Methods. The results shown are of a single experiment with 3 independent replicates cell viability was measured by CellTiter-Blue assay. The graph depicts cell viability at 72 hours. Cell viability in the vehicle control was considered as to be 100%.

Product Citations (1)

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  A High Notch Pathway Activation Predicts Response to γ Secretase Inhibitors in Proneural Subtype of Glioma Tumor Initiating Cells. [Norihiko Saito, et al. STEM CELLS 2013;32(1):301-12]