DAPT (GSI-IX)

Catalog No.S2215

DAPT (GSI-IX) is a novel γ-secretase inhibitor, which inhibits Aβ production with IC50 of 20 nM in HEK 293 cells.

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DAPT (GSI-IX) Chemical Structure

DAPT (GSI-IX) Chemical Structure
Molecular Weight: 432.46

Validation & Quality Control

Customer Product Validation(4)

Quality Control & MSDS

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Product Description

Biological Activity

Description DAPT (GSI-IX) is a novel γ-secretase inhibitor, which inhibits Aβ production with IC50 of 20 nM in HEK 293 cells.
Targets [1]
(HEK 293 cells)
γ secretase(Aβ) [1]
(HEK 293 cells)
IC50 20 nM 20 nM
In vitro In human primary neuronal cultures, DAPT also shows inhibitory effects on Aβ production with IC50 of 115 nM and 200 nM respectively for Aβ total and Aβ42, which is 5-10-fold lower than is observed in HEK 293 cells. [1] A recent study shows that DAPT inhibits the proliferation of SK-MES-1 cells in a concentration-dependent manner with IC50 of 11.3 μM. In addition, DAPT also induces caspase-dependent and caspase-independent apoptosis in lung squamous cell carcinoma cells by inhibiting Notch receptor signaling pathway. [2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
A549 CD133−NUHUdG1JT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MYSyJO69VQ>?NGDyOHo1QCCqNH73UYZmdmijbnPld{Bk\WyuIHfyc5d1cCCrbnjpZol1cW:wIHnu[JVk\WRiYomgR2RFWA>?NEDZe3czPDVyMkm0PS=>
A549 CD133+MVTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?NGC4eWMzKM7:TR?=MnfNOFghcA>?M{XObIVvcGGwY3XzJINmdGxiZ4Lve5RpKGmwaHnibZRqd25iaX7keYNm\CCkeTDDSGRRMn73NlQ2ODJ7NEm=
HT29 MnLQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M2rJflAvPS15NTFOwG0>MU[xNk8zPC92ODDoMmG5SG1UVw>?NXzKb2tWcW6qaXLpeJMhfGinIHPlcIwh\3Kxd4ToJIlvKGFiY3;uZ4VvfHKjdHnvckBu[W6wZYK=NILwUmYzPTJ3N{m0OS=>
SHG-44NVGwTHZET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=Mny2NE42NTFyIN88US=>NW[3c4MyOS13IHS=Mlj3bY5pcWKrdIOgeIhmKGOnbHygeoli[mmuaYT5JIF1KHSqZTDvdJRqdWGuIHPvcoNmdnS{YYTpc44hd2ZiMTFOwG0>NYHV[3BJOjVyNkOyPFU>
MG63MmDpSpVv[3Srb36gRZN{[Xl?Mn\pNVAxKM7:TR?=NE\E[2QzPCCqM4PKVGROW09?M3rkbIRme2Wwc3n0bZpmeyC2aHWgZ4VtdCCuaX7lJJRwKGOrc4DsZZRqdiC2cnXheI1mdnR?MV[yOFg6PDJ7Nx?=
Saos-2MmnESpVv[3Srb36gRZN{[Xl?M37MTFExOCEQvF2=Mln6NlQhcA>?NHPpWVdFVVORNWPqbW5O\GW|ZX7zbZRqgmW|IITo[UBk\WyuIHzpcoUhfG9iY3nzdIxifGmwIITy[YF1dWWwdB?=MofFNlQ5QTR{OUe=
U251NHfBXVRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NUXZc4FUOiEQvF2=M4GwZ|Q5KGh?M4T4SGROW09?M4fmZZN1emWwZ4To[Y5{yqC2LVHVR2IucW6mdXPl[EBk\WyuIHfyc5d1cCC|dYDwdoV{e2mxbh?=MWSyOFc6OzNzMx?=
U87 NFLTR5FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=M{XTN|Ih|ryPM{D2fVQ5KGh?NGW0WY5FVVORMXzzeJJmdme2aHXud:KhfC2DVVPCMYlv\HWlZXSgZ4VtdCCpcn;3eIghe3WycILld5Nqd25?MYqyOFc6OzNzMx?=
U251NUe0coRTTnWwY4Tpc44hSXO|YYm=MkDhNkDPxE1?Mk[wOFghcA>?NFnXbVdFVVORMnn6Zoxw[2u|wrD0MWFWS0JvaX7keYNm\CCjY4TpeoF1cW:wIH;mJJRp\SCyM{igUWFRUy:PQWDLRXBMOi:Kc4CyO{Bx[XSqd3H5JIFv\CCrbnjpZol1eyCneIDy[ZN{cW:wIH;mJG5KS0RzNGXjUFgzPDd7M{OxNy=>
U87 NFK5RZBHfW6ldHnvckBCe3OjeR?=NWLtc49zOiEQvF2=NFXqSoY1QCCqMWLEUXNQNYDTTmdj[myxY3vzxsB1NUGXQ1KtbY5lfWOnZDDhZ5RqfmG2aX;uJI9nKHSqZTDwN|ghVUGSSz;NRXBMSVCNMj;Id5AzPyCyYYToe4F6KGGwZDDpcohq[mm2czDlfJBz\XO|aX;uJI9nKE6LQ1SxM{T5ZVI1Pzl|M{Gz
A549 M2PUZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NVLRSGMyOTBizszNNGDRNXMzPGh?NGn4fZNl\WO{ZXHz[ZMhfGinIHPlcIwhfmmjYnnsbZR6KGOxbXLpcoVlKHerdHigVHRGMYiyN|Y4OTZzOR?=
GC-B Mnf4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?MYe2MlI2NTFyMDFOwG0>M2\6b|I1KGh?MYjEUXNQNYftfmFKcW6qaXLpeJMhfGinIHPlcIwh\3Kxd4ToJIlvKGFiZH;z[U1l\XCnbnTlcpQhdWGwbnXyNYHlc|FwOTl3NEK0OFY>

... Click to View More Cell Line Experimental Data

In vivo DAPT administration (100mg/kg) leads to a robust and sustained pharmacodynamic effect in PDAPP mice that DAPT levels in the brain exceeds 100 ng/g within 1 hour and persists up to 18 hours after administration, with peak levels of 490 ng/g observed after 3 hour. And during the period, DAPT (100 mg/kg) also reduces the cortical total Aβ and Aβ42 in a dose-dependent manner with a 50% reduction. [1] In rat cerebral cortexes, DAPT (40 mg/kg) suppresses the LPS-induced activity of γ-secretase and increases the cell apoptosis with the prolonged neuroinflammation. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro Aβ reduction assays Human embryonic kidney cells (American Type Culture Collection CRL-1573), transfected with the gene for APP751 (HEK 293) are used for routine Aβ reduction assays. Cells are plated in 96-well plates and allowed to adhere overnight in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum. DAPT are diluted from stock solutions in dimethylsulfoxide (DMSO) to yield a final concentration equal to 0.1% DMSO in media. Cells are pre-treated for 2 hours at 37 °C with DAPT, media are aspirated off and fresh compound solutions applied. After an additional 2-hour treatment period, conditioned media is drawn off and analyzed by a sandwich ELISA (266–3D6) specific for total Aβ. Reduction of Aβ production is measured relative to control cells treated with 0.1% DMSO and expressed as a percentage inhibition. Data from at least six doses in duplicate are fitted to a four-parameter logistical model using XLfit software in order to determine potency. Human and PDAPP mouse neuronal cultures are grown in serum-free media to enhance their neuronal characteristics, and appeared to be greater than 90% neurons after maturation prior to use. Conditioned media to establish baseline Aβ values are collected by adding fresh media to each well and incubated for 24 hours at 37 °C in the absence of DAPT. Cultures are then treated with fresh media containing DAPT at the desired range of concentrations for an additional 24 hours at 37 °C, and conditioned media collected. For the measurement of total Aβ, samples are analyzed with the same ELISA (266–3D6) as used for the HEK 293 cell assays. Analyses of samples for Aβ42 production are performed by a separate ELISA (21F12–3D6) that utilizes a capture antibody specific for the Aβ42 C-terminus. Inhibition of production for both total Aβ and Aβ42 are determined by the difference between the values for the compound treatment and baseline periods. After plotting percentage inhibition versus DAPT concentration, data are analyzed with XLfit software, as above, to determine potency.

Cell Assay: [2]

Cell lines SK-MES-1
Concentrations 2.5 μM to 160 μM
Incubation Time 72 hours
Method Cells are seeded into 96-well plates and exposed to 0.1% DMSO or DAPT at concentrations in the range of 2.5 μM–160 μM for 72 hours. Cytotoxicity is determined with 3-(4, 5)-dimethylthiahiazo-(-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) dye reduction assay with minor modifications. Briefly, after incubation with DAPT, 20 μL MTT solution (5 mg/mL in PBS) is added to 180 μL medium in each well and plates are incubated for 4 hours at 37 °C, and subsequently 150 μL DMSO is added to each well, and mixed by shaking at room temperature for 15 minutes. Absorption is measured by an enzyme-linked immunosorbent assay at 490 nm to determine absorbance values. α-MEM supplemented with the same amount of MTT solution and solvent is used as blank solution. The IC50 value is calculated using PROBIT program in SPSS.

Animal Study: [1]

Animal Models Heterozygous PDAPP transgenic mice overexpressing the APPV717F mutant form of the amyloid precursor protein.
Formulation DAPT is dissolved in corn oil, 5% (v/v) ethanol.
Dosages ≤100 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Dovey HF, et al. J Neurochem. 2001, 76(1), 173-181.

[2] Cao H, et al. APMIS. 2012, 120(6), 441-450.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02605447 Recruiting Coronary Artery Disease Boston Scientific Corporation January 2016 Phase 4
NCT02601157 Recruiting Stable Angina|Unstable Angina|Non-ST Segment Elevation Myocardial Infarction Seoul National University Hospital|B. Braun Korea Co., Ltd. December 2015 Phase 4
NCT02619760 Recruiting Coronary Artery Disease Kyoto University, Graduate School of Medicine December 2015 Phase 4
NCT02609698 Recruiting Stable Angina, Unstable Angina, Silent Coronary Ischemia, Coronary Artery Disease Ajou University School of Medicine|B. Braun Korea Co., Ltd. August 2015 Phase 4
NCT02513810 Recruiting Coronary Artery Disease Yonsei University July 2015 --

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Chemical Information

Download DAPT (GSI-IX) SDF
Molecular Weight (MW) 432.46
Formula

C23H26F2N2O4

CAS No. 208255-80-5
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms LY-374973
Solubility (25°C) * In vitro DMSO 86 mg/mL (198.86 mM)
Ethanol 50 mg/mL (115.61 mM)
Water <1 mg/mL (<1 mM)
In vivo 5% DMSO+95% Corn oil 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl)acetamido)propanamido)-2-phenylacetate

Customer Product Validation (4)


Click to enlarge
Rating
Source Oncogene 2014 10.1038/onc.2014.319. DAPT (GSI-IX) purchased from Selleck
Method Western blot
Cell Lines Notch1 ΔE cells
Concentrations 10 uM
Incubation Time 3 days
Results Indeed, depleted SUMO1 were observed in NOTCH1 cells compared with control MCF10A cells. Western blotting showing increased unconjugated SUMO1 levels in Notch1 ΔE cells treated with 10 uM DAPT for 3 days.

Click to enlarge
Rating
Source Stem Cells 2014 32(1), 301-12. DAPT (GSI-IX) purchased from Selleck
Method Western blot
Cell Lines Glioma tumor-initiating cells
Concentrations 5-50 uM
Incubation Time 48 h
Results This cleavage can release the NICD, and released NICD translocates into the nucleus and binds CBF-1 to activate Notch targeting genes, such as the Hes genes, to antagonize the activity of proneural genes like Mash1, Math, NeuroD, and Neurogenins. As shown in Figure , DAPT, BMS-708163 inhibited expression of NICD, Hes1, Hes3, and Hes5 in a time- and dose-dependent manner.

Click to enlarge
Rating
Source Dis Model Mech 2013 6(6), 1494-506. DAPT (GSI-IX) purchased from Selleck
Method Western blot
Cell Lines R26PR-derived T-ALLs
Concentrations 1 uM
Incubation Time 24, 48, 72 h
Results To determine the role of NOTCH1 in driving proliferation of R26PR-derived T-ALLs, we cultured a tumor cell line derived from these animals in the presence of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), which inhibits the release of NICD from the cell membrane. Tumor cells cultured in DAPT were unable to proliferate (C), with a concomitant decrease in NICD expression (D) when compared with the parental, untreated cell line and DMSO-vehicle-treated control culture.

Click to enlarge
Rating
Source Invest Ophth Vis Sci 2012 53,12 . DAPT (GSI-IX) purchased from Selleck
Method In Vitro Scratch Assay
Cell Lines Primary human corneal epithelial cells/HCE-T cell line
Concentrations 0.1-50 μM
Incubation Time 48 h
Results Notch inhibition using DAPT and using Notch1-shRNA both enhanced in vitro migration in scratch and transwell migration assays.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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