LY411575

Catalog No.S2714

For research use only.

LY411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), also inhibits Notch cleavage with IC50 of 0.39 nM in APP or NΔE expressing HEK293 cells. LY411575 induces apoptosis.

LY411575 Chemical Structure

CAS No. 209984-57-6

Selleck's LY411575 has been cited by 23 publications

Purity & Quality Control

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Biological Activity

Description LY411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/cell-based), also inhibits Notch cleavage with IC50 of 0.39 nM in APP or NΔE expressing HEK293 cells. LY411575 induces apoptosis.
Targets
γ secretase (membrane-based) [1]
(HEK293 cells expressing either APP or NΔE)
γ secretase (cell-based) [1]
(HEK293 cells expressing either APP or NΔE)
Notch S3 cleavage [1]
(HEK293 cells expressing either APP or NΔE)
0.078 nM 0.082 nM 0.39 nM
In vitro

LY-411575 inhibits γ-secretase which can be assessed by the substrates like amyloid precursor protein (APP) and Notch S3 cleavage. [1] LY-411575, which blocks Notch activation, results in apoptosis in primary and immortalized KS cells. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
CHO M4nlXWZ2dmO2aX;uJIF{e2G7 MXSyOEBpenN? NIX0epVT\WS3Y4Tpc44hd2ZiaIXtZY4hf2muZDD0fZBmKFCVMT3pcoR2[2WmIHHtfYxwcWRiYnX0ZU01OCCuZY\lcEBqdiCFSF:gZ4VtdHNib4\ldoV5eHKnc4PpcochcHWvYX6gRXBRPzVzIHHmeIVzKDJ2IHjyd{BjgSCuaYH1bYQheGijc3Wg[Yxm[3S{b3Po[Y1qdHWvaX7ld4NmdmOnIHHzd4F6KHKnbHH0bZZmKHSxIHPvcpRzd2xuIFXDOVAhRSByLkCwNFEyPCEQvF2u MnrOQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOTd3N{OzOFYoRjF5NUezN|Q3RC:jPh?=
HEK293 MWDGeY5kfGmxbjDhd5NigQ>? Moi0TY5pcWKrdHnvckBw\iCpYX3tZUB{\WO{ZYThd4UhcW5iaIXtZY4hUEWNMkmzJINmdGy|IHHzd4V{e2WmIHHzJIFugWyxaXSgZoV1[SB2MDDwdo9lfWO2aX;uMEBGSzVyIE2gNE4xODBzMUmg{txONg>? Mn2wQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOTd3N{OzOFYoRjF5NUezN|Q3RC:jPh?=
CHO M{X3SGZ2dmO2aX;uJIF{e2G7 NESwVYIzPCCqcoO= NXzJbWFtWmWmdXP0bY9vKG:oIHj1cYFvKHerbHSgeJlx\SCSU{GtbY5lfWOnZDDhcZltd2mmIHLleIEuPDJibHX2[YwhcW5iQ1jPJINmdGy|IH;2[ZJmgHC{ZYPzbY5oKGi3bXHuJGFRWDd3MTDh[pRmeiB{NDDodpMh[nlibHnxeYllKHCqYYPlJIVt\WO2cn;jbIVucWy3bXnu[ZNk\W6lZTDhd5NigSC{ZXzheIl3\SC2bzDjc451em:uLDDFR|UxKD1iMD6wNFAyOzVizszNMi=> Ml;0QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOTd3N{OzOFYoRjF5NUezN|Q3RC:jPh?=
HEK293 M{DYZWZ2dmO2aX;uJIF{e2G7 M{TUfVI1KGi{cx?= NXnCU4ZWUW6qaXLpeIlwdiCxZjDoeY1idiCpYX3tZU1{\WO{ZYThd4Uh\XiycnXzd4VlKGmwIFjFT|I6OyClZXzsd{B2e2mwZzDOc5RkcDFvVmCxOk1I[Wx2IHHzJJN2[nO2cnH0[UBi\nSncjCyOEBpenNiYomgRpJq\2i2LVfsc{BtfWOrZnXyZZNmKHKncH;yeIVzKGenbnWgZZN{[XluIFnDOVAhRSByLkCwNFMh|ryPLh?= MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTN3OUW2OUc,Ojl|NUm1OlU9N2F-
CHO MkW0SpVv[3Srb36gZZN{[Xl? NUfpe4pFOjRiaILz Mne4VoVlfWO2aX;uJI9nKGi3bXHuJHBUOSCmZXz0ZUBmgG:wOTDteZRidnRvaX7keYNm\CCjbYnsc4llKGKndHGtOFIhdGW4ZXygbY4hS0iRIHPlcIx{KG:4ZYLlfJBz\XO|aX7nJIh2dWGwIFHQVFc2OWGodHXyJFI1KGi{czDifUBtcXG3aXSgdIhie2ViZXzlZ5Rzd2OqZX3pcJVucW6nc3PlcoNmKGG|c3H5JJJmdGG2aY\lJJRwKGOxboTyc4wtKEWFNUCgQUAxNjByMEO1NkDPxE1w MoDMQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOTd3N{OzOFYoRjF5NUezN|Q3RC:jPh?=
CHO MlnJSpVv[3Srb36gZZN{[Xl? M3\KPFI1KGi{cx?= NYXGVnRtWmWmdXP0bY9vKG:oIHj1cYFvKFCVMTDk[Yx1[SCneH;uPUBufXSjboStbY5lfWOnZDDhcZltd2mmIHLleIEuPDBibHX2[YwhcW5iQ1jPJINmdGy|IH;2[ZJmgHC{ZYPzbY5oKGi3bXHuJGFRWDd3MXHmeIVzKDJ2IHjyd{BjgSCuaYH1bYQheGijc3Wg[Yxm[3S{b3Po[Y1qdHWvaX7ld4NmdmOnIHHzd4F6KHKnbHH0bZZmKHSxIHPvcpRzd2xuIFXDOVAhRSByLkCwNFM2QCEQvF2u M{\HNVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzF5NUezN|Q3Lz5zN{W3N|M1PjxxYU6=
SH-SY5Y MWfGeY5kfGmxbjDhd5NigQ>? M1GyV2lvcGmkaYTpc44hd2ZiZ3HtcYEhe2WlcnX0ZZNmNW2nZHnheIVlKGGveXzvbYQh[mW2YTCoNUB1dyB2MDmgdJJw\HWldHnvckBqdiCqdX3hckBUUC2VWUXZJINmdGy|LDDJR|UxKD1iMD6wNFEh|ryPLh?= NVW5VZdmRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMUm2PVQ1PjdpPkG5Olk1PDZ5PD;hQi=>
SH-SY5Y MYjGeY5kfGmxbjDhd5NigQ>? Mn[ySIl{eGyjY3Xt[Y51KG:oIGuzTH02NWOqbH;yc{1PNShqMmOsN3IqNTVuNTy1MZRzcW[udX;yc{0yNWi7ZILvfJkuOy2vZYTofYxx\W62YX6tNk16dCm2aHnvdIhmdmVvMj3zeYxnd26jbXnk[UBnem:vIHfhcY1iKHOnY4LleIF{\SCrbjDoeY1idiCVSD3TXVV[KGOnbHzzJIJ6KGOxbYDleIl1cX[nIHLpcoRqdmdiYYPzZZktKEmFNUCgQUAxNjByMTFOwG0v Mn\UQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOTl4OUS0OlcoRjF7Nkm0OFY4RC:jPh?=
HEK293 NYrs[mdFTnWwY4Tpc44h[XO|YYm= NVzHdJZIOjRiaILz M{XSemlvcGmkaYTpc44hd2ZiaIXtZY4hW1CSTELhJIV5eHKnc4Pl[EBqdiCKRVuyPVMh[2WubIOgeZNqdmdiR1HMOE1XWDF4IH\1d4VlXE6IYXzwbIEhMDFidH:gO|YqNU6WRjDhd{B{fWK|dILheIUh[W[2ZYKgNlQhcHK|IHL5JGJzcWeqdD3HcI8hdHWlaX\ldoF{\SC{ZYDvdpRmeiCpZX7lJIF{e2G7LDDJR|UxKD1iMD6wNUDPxE1w NVLhfGlsRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkmzOVk2PjVpPkK5N|U6PTZ3PD;hQi=>
U2OS MmLkSpVv[3Srb36gZZN{[Xl? MlHFNlQhcHK| M{PSfWlvcGmkaYTpc44hd2ZiaIXtZY4hW1CSIHX4dJJme3OnZDDpckBpfW2jbjDVNm9UKGOnbHzzJJV{cW6pIFXHSnAudGGkZXzl[EBGdn[VaXfT[ZEuW0WDUDDhd{B{fWK|dILheIUh[W[2ZYKgNlQhcHK|IHL5JGhw\WOqc4Sgd5RicW6rbnegZoF{\WRiaHnnbEBkd262ZX70JIlu[WerbnegZZN{[XluIFnDOVAhRSByLkC1JO69VS5? MWW8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTN3OUW2OUc,Ojl|NUm1OlU9N2F-
HEK293 NFHUV2RHfW6ldHnvckBie3OjeR?= NYjCWnhmOyCmYYnz NHjEWplOd2S3bHH0bY9vKG:oIHfhcY1iNXOnY4LleIF{\SCrbjDISWszQTNiY3XscJMh\XiycnXzd4lv\yCpdXnu[YEheGmpIGP3[YRqe2hibYX0ZY51KFOIVj3BVHA3QTW|dzDjc4V5eHKnc4PpcochTEyONDDhd5Nme3OnZDDhd{BqdmirYnn0bY9vKG:oIH7veINpKHC{b3Pld5NqdmdiaX6gbJVu[W5iVFW2O|Eh[2WubIOgZYZ1\XJiMzDkZZl{KGK7IHT1ZYwu[2WubDDseYNq\mW{YYPlJJJmeG:{dHXyJIdmdmViYYPzZZktKEmFNUCgQUAyNjJizszNMi=> MXG8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDF|OUW4N{c,OjRzM{m1PFM9N2F-
SH-SY5Y MVjGeY5kfGmxbjDhd5NigQ>? MnjaNUBpeg>? M132T2Rqe3CuYXPlcYVvfCCxZjDbN2heMFNrLUWtZ4htd3KxLV6tLFMu\XSqeXytNU1pgWS{b4j5dIVvfGGwLUKtfYwqfGirb4Do[Y5mNTJvc4Xs[o9v[W2rZHWg[pJwdSCpYX3tZUB{\WO{ZYThd4UhcW5iaIXtZY4hW0hvU2m1XUBk\WyuczDh[pRmeiBzIHjy NVK3eIN1RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMUm0OFMzOjhpPkG5OFQ{OjJ6PD;hQi=>
H4 Ml3TSpVv[3Srb36gZZN{[Xl? NETjfnkyODBibl2= NFTkXVIyPiCqcoO= NYTLSYM2UW6qaXLpeIlwdiCxZjDnZY1u[SC|ZXPy[ZRie2ViZYjwdoV{e2WmIHnuJIh2dWGwIFi0JINmdGy|IHX4dJJme3OrbnegRnJKNUN7OTDmeZNqd25icILveIVqdiCjc4Pld5Nm\CCjczDDPVkh\nKjZ33lcpQh[WOldX31cIF1cW:wIH\yZYdu\W62IHH0JFExOCCwTTDpcoN2[mG2ZXSg[o9zKDF4IHjyd{BqdiCkeTDpcY12dm:kbH;0 MX:8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzF6MUWwNkc,OjNzOEG1NFI9N2F-
H4 NX7tR2h7TnWwY4Tpc44h[XO|YYm= MXyxNEB2VQ>? NYfDO2NMOTZiaILz NHvoZ4NKdmirYnn0bY9vKG:oIHfhcY1iKHOnY4LleIF{\SCneIDy[ZN{\WRiaX6gbJVu[W5iSESgZ4VtdHNiYYPz[ZN{\WRiYYOgdoVlfWO2aX;uJIlvKEN6MzDs[ZZmdHNiYYSgNVAhfU1iaX7jeYJifGWmIH\vdkAyPiCqcoOgZpkhcW2vdX7vZoxwfA>? MWe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzF6MUWwNkc,OjNzOEG1NFI9N2F-
H4 NXnaUHNoTnWwY4Tpc44h[XO|YYm= MmfTNVAhfU1? MYKxOkBpenN? MoHPTY5pcWKrdHnvckBw\iCpYX3tZUB{\WO{ZYThd4Uh\XiycnXzd4VlKGmwIHj1cYFvKEh2IHPlcIx{KGG|c3Xzd4VlKGG|IILl[JVkfGmxbjDpckBEXEZibHX2[Yx{KGG2IEGwJJVOKGmwY4XiZZRm\CCob4KgNVYhcHK|IHL5JIludXWwb3Lsc5Q> NITDUVE9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{G4NVUxOid-MkOxPFE2ODJ:L3G+
In vivo 10 mg/kg oral dose of LY-411575 decreases brain and plasma Aβ40 and -42 dose-dependently. [1] LY-411575 reduces cortical Aβ40 in young (preplaque) transgenic CRND8 mice (ED50 ≈ 0.6 mg/kg) and produces significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window is similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects are reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411575 reduces cortical Aβ40 by 69% without inducing intestinal effects, although a previously unreported change in coat color is observed. [3]

Protocol (from reference)

Kinase Assay:

[1]

  • Assays for Aβ and NICD:

    Procedures for measuring γ-secretase activity in membranes prepared from HEK293 cells expressing APP have been described previously (Zhang L et al Biochemistry 40, 5049-5055). Intact HEK293 cells expressing either APP or NΔE are treated with various concentrations of LY- 411,575 for 4 hours at 37 °C. In the case of cells expressing NΔE, cells are lysed, the cell lysates are separated on a 4-12% NuPAGE gel, and the processed NICD fragment is detected via Western blot with a cleavage site-specific antibody. The inhibition of NICD production is quantified by spot densitometric analysis using FluorChem. In the case of cells expressing APP, the conditioned medium is collected, centrifuged at 10,000 × g for 5 minutes to remove cell debris, and stored at -20 °C prior to the determination of Aβ levels. Aβ40 and -42 produced in HEK293 membrane- and cell-based assays, as well as plasma Aβ40 and cortex Aβ40 from TgCRND8 mice, are analyzed without pretreatment using an electrochemiluminescence detection-based immunoassay. Plasma Aβ42 is measured by enzyme-linked immunosorbent assay. A commercially available enzyme-linked immunosorbent assay kit is used to measure cortex Aβ42 according to the manufacturer''s instructions.

Cell Research:

[2]

  • Cell lines: primary and immortalized KS cells
  • Concentrations: 500 μM
  • Incubation Time: 24 hours
  • Method:

    DNA/PI staining is performed using standard methodologies. Briefly, 1 × 106 cells are permeabilized with 100% ethanol in the presence of 15% FBS. The cells are washed and then treated for 15 minutes at 37 °C with 10 mg/mL RNAse. PI (5 mg/mL) is added, and the cells incubated for 1 hour at 4 °C prior to analysis by flow cytometry with 10 000 cells analysed per gated determination. The results are confirmed using the Immunotech Annexin V staining kit following the manufacturers’ instructions. At least three independent experiments are performed showing similar results.

  • (Only for Reference)
Animal Research:

[1]

  • Animal Models: TgCRND8 mice model
  • Dosages: 1-10 mg/kg
  • Administration: Orally
  • (Only for Reference)

Solubility (25°C)

In vitro

DMSO 95 mg/mL
(198.13 mM)
Ethanol 13 mg/mL
(27.11 mM)
Water Insoluble

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing.

30 mg/mL

* 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 Information

Molecular Weight 479.48
Formula

C26H23F2N3O4

CAS No. 209984-57-6
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)C(C4=CC(=CC(=C4)F)F)O

In vivo Formulation Calculator (Clear solution)

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Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Molarity Calculator

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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.

Handling Instructions

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Frequently Asked Questions

Question 1:
Does this inhibitor act on beta-secretase?.

Answer:
LY411575 has been reported to inhibit gamma-secretase, currently, there is no publication reporting its inhibition on beta-secreatse.

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