EX 527 (Selisistat)

Catalog No.S1541

EX 527 (Selisistat) is a potent and selective SIRT1 inhibitor with IC50 of 38 nM in a cell-free assay, exhibits >200-fold selectivity against SIRT2 and SIRT3. Phase 2.

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EX 527 (Selisistat) Chemical Structure

EX 527 (Selisistat) Chemical Structure
Molecular Weight: 248.71

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Product Description

Biological Activity

Description EX 527 (Selisistat) is a potent and selective SIRT1 inhibitor with IC50 of 38 nM in a cell-free assay, exhibits >200-fold selectivity against SIRT2 and SIRT3. Phase 2.
Targets SIRT1 [1]
(Cell-free assay)
IC50 38 nM
In vitro EX 527 exhibits potently inhibitory effect against SIRT1 deacetylase activity in a concentration-dependent manner with an IC50 of 38 nM, displays much lower activity against SIRT2 and SIRT3 with IC50 values of 19.6 μM and 48.7 μM, respectively. EX 527 does not inhibit SIRT4-7 and class I/II HDAC activity at concentrations up to 100 μM. EX-527 alone (1 μM) has no detectable effect on the acetylation of p53 lysine 382 in NCI-H460 cells. EX-527 significantly increases the amount of acetylated p53 in NCI-H460 cells, human mammary epithelial cells, U-2 OS and MCF-7 cells subjected to genotoxic agents such as Etoposide, Doxorubicin, Hydroxyurea, and Hydrogen peroxide, which is more effective than that caused by Nicotinamide (5 mM). But surprisingly EX 527 does not result in detectable effects on p53-controled gene expression, cell survival, or cell proliferation. [1] EX 527 causes a 90% increase in cell number of HCT116 cells after 7 days in the condition of 0.1% serum but not 10% serum, suggesting that SIRT1 is a significant regulator of cell proliferation during growth factor deprivation conditions. [2] EX 527 abrogates resveratrol effects on glucose responses, and prevents resveratrol-induced up-regulation of Glut2, glucokinase, Pdx-1, and Tfam in INS-1E Cells, due to the opposite effect of EX 527 and resveratrol on SIRT1 deacetylase activity. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
PlateletsNHnSVIVCeG:ydH;zbZMhSXO|YYm=MorWNVAwPTBizszNNUThN5NYOTBibXnuMUHEUXNQMlPwbY5kemWjc3XzJHJQWyCuZY\lcEBqdiCjIHTvd4Uu\GWyZX7k[Y51KG2jbn7ldi=>NFzPRnEzPTh{OUS5OS=>
HEK 293MkHsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?M4q3N|I1KGh?NWnIR4NNUUN3ME25O{44KMLzIEiuNUDPxE1?NYK0cpJvOjR7OUi0Nlc>
HeLaNXvmZ|FKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=Mlz4NlQhcA>?NG\6XGVKSzVyPUO3MlnDqMLzwrCxMlgh|ryPMV[yOFk6QDR{Nx?=
HEK 293M2XtfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7M135dVQ5KGh?M3zzXGlEPTB;NkmuNOKhyrIEoECuO{DPxE1?Ml75NlQ6QTh2Mke=
HeLaNVvMPWNmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=MonaOFghcA>?M2nFbGlEPTB;OD65xsDDucLiMT65JO69VQ>?NF7RbIYzPDl7OESyOy=>
RMECsMn7ERZBweHSxc3nzJGF{e2G7Mnv4NVDDqM7:TR?=MYGyOOKhcA>?MWPheJRmdnWjdHXzJJRp\SCjboTpMYFxd3C2b4TpZ{Bm\m[nY4Sgc4YhTGW|LVe=M4PlbFI1PDh4MUS3
HUVECsMojnRZBweHSxc3nzJGF{e2G7MlPMNVDDqM7:TR?=NE[zbZIzPCCqNITpdmhjd2yrc3jld{B1cGVicILveIVkfGm4ZTDl[oZm[3Rib3[gdoV{fmW{YYTyc4whcW5iY3XscEB3cWGkaXzpeJk>NFrVV|EzOzN3OEmyPC=>
K562MXnGeY5kfGmxbjDBd5NigQ>?NYnueIc6OC5zLUGg{txONVLmO5RpOiCqNV3UZnBte3SrbYXsZZRmeyCQcn[yMYRmeGWwZHXueEBo\W6nIITyZY5{[3KrcITpc44>MXOyNVE6PjR7Nx?=
INS-1EM2nwb2Z2dmO2aX;uJGF{e2G7NIHsOVUyKM7:bR?=NGHN[VMzPCCqMWXwdoV3\W62czDy[ZN3\XKjdILvcE1qdmS3Y3XkJJVxNXKnZ4XsZZRqd25ib3dCpGdtfXR{LDDncJVkd2urbnHz[UxR\HhvMTygZY5lyqCWZnHtM1rnS|IyOTZ|OUS2
MCF-7 MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?M{LvflAuOTByIN88US=>MoC4NlQwPDhxN{KgbC=>MYfEUXNQM17MPJJmeHKnc4Pld{Bk\WyuIIDyc4xq\mW{YYTpc44h[XRidHjlJINwdmOnboTyZZRqd25i4polNVAxKM7:TR?=MWOyNFM4OTdyOR?=
NCI-H460 MlT6SpVv[3Srb36gRZN{[Xl?NXnaW3FHOSEQvH2=MXS2JIg>M4juUmROW09?M2\JPJBzd2S3Y3XzJIEh[2:wY3XueJJifGmxbj3k[ZBmdmSnboSgbY5kemWjc3WgbY4hfGinIHHtc5VvfCCxZjDhZ4V1gWyjdHXkJJA2Ow>?MY[xOlM2PDZ5Nx?=

... Click to View More Cell Line Experimental Data

In vivo Administration of EX 527 (~10 μg) to rats increases hypothalamic acetyl-p53 levels by inhibiting hypothalamic SIRT1 activity. Co-administration of EX 527 with ghrelin markedly blunts the orexigenic action of ghrelin by decreasing the pAMPK levels, increasing the ACC levels, and abolishing the higher expression of the transcription factors FoxO1, pCREB, and Bsx and the neuropeptides NPY and AgRP in the hypothalamic arcuate nucleus. [4]
Features Greater potency, specificity, stability, and lower toxicity than other inhibitors of SIRT1 catalytic activity identified to date.

Protocol(Only for Reference)

Kinase Assay: [1]

Inhibition of GST-SIRT1 deacetylase activity 293T cells are transiently transfected with GST-tagged human SIRT1 in the pDEST27 Gateway vector using FuGENE-6. After 48 hours, the cells are lysed with 50 mM Tris, pH 8.0, 120 mM NaCl, 1 mM EDTA, and 0.5% Nonidet P-40, supplemented with Complete Mini protease inhibitor cocktail tablets. GST-SIRT1 is purified from lysates using glutathione-Sepharose beads and washed extensively in the above buffer. The deacetylation assay is performed with approximately 30 ng of GST-SIRT1 in the presence of EX 527 (48 pM to 100 μM). Deacetylation is measured using the Fluor de Lys kit using a fluorogenic peptide encompassing residues 379 to 382 of p53, acetylated on lysine 382. The acetylated lysine residue is coupled to an aminomethylcoumarin moiety. The peptide is deacetylated by SIRT1, followed by the addition of a proteolytic developer that releases the fluorescent aminomethylcoumarin. Briefly, enzyme preparations are incubated with 170 μM NAD+ and 100 μM p53 fluorogenic peptide for 45 minutes at 37 °C followed by incubation in developer for 15 minutes at 37 °C. Fluorescence is measured by excitation at 360 nm and emission at 460 nm and enzymatic activity is expressed in relative fluorescence units.

Cell Assay: [1]

Cell lines NCI-H460, MCF-7, U-2 OS and HMEC
Concentrations Dissolved in DMSO, final concentration 1 μM
Incubation Time 48 or 72 hours
Method For viability assays, cells are treated with EX 527 for 48 hours. Cell viability is then determined using the Cell Titer-Glo luminescent assay, which measures total ATP level as an index of cell number. Luminescence is measured on a Luminoskan Ascent. For the proliferation assay, 0.5 μCi/mL of [14C]thymidine is added to the medium immediately after EX 527. Plates are counted at 48 hours (HMEC) or 72 hours (NCI-H460, MCF-7, and U-2 OS cells) in a Microbeta liquid scintillation counter. Thymidine incorporated by the cells is detected by proximity to the scintillant in the base of the Cytostar-T tissue culture plate.

Animal Study: [4]

Animal Models Male Sprague-Dawley rats
Formulation Dissolved in DMSO in a total volume of 5 μL
Dosages ~5 μg/rat
Administration Intracerebroventricular injection

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] Solomon JM, et al. Mol Cell Biol, 2006, 26(1), 28-38.

[2] Kabra N, et al. J Biol Chem, 2009, 284(27), 18210-18217.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01485965 Completed Huntingtons Disease Siena Biotech S.p.A. November 2011 Phase 1
NCT01521585 Completed Huntingtons Disease Siena Biotech S.p.A. November 2011 Phase 2
NCT01485952 Completed Huntington Disease Siena Biotech S.p.A.|Seventh Framework Programme|European  ...more Siena Biotech S.p.A.|Seventh Framework Programme|European Huntingtons Disease Network March 2011 Phase 1
NCT01521832 Completed Huntingtons Disease Siena Biotech S.p.A. October 2009 Phase 1

Chemical Information

Download EX 527 (Selisistat) SDF
Molecular Weight (MW) 248.71
Formula

C13H13ClN2O

CAS No. 49843-98-3
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms SEN0014196
Solubility (25°C) * In vitro DMSO 50 mg/mL (201.03 mM)
Ethanol 18 mg/mL (72.37 mM)
Water <1 mg/mL
In vivo 1% DMSO+30% polyethylene glycol+1% Tween 80 14 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)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide

Frequently Asked Questions

  • Question 1
    what is the extinction coefficient of S1541 WX527?

    Answer: The extinction coefficient of S1541 EX-527 is 1421.650635.

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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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