Details
| Stereochemistry | RACEMIC |
| Molecular Formula | C13H13ClN2O |
| Molecular Weight | 248.708 |
| Optical Activity | ( + / - ) |
| Defined Stereocenters | 0 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(=O)C1CCCC2=C1NC3=C2C=C(Cl)C=C3
InChI
InChIKey=FUZYTVDVLBBXDL-UHFFFAOYSA-N
InChI=1S/C13H13ClN2O/c14-7-4-5-11-10(6-7)8-2-1-3-9(13(15)17)12(8)16-11/h4-6,9,16H,1-3H2,(H2,15,17)
| Molecular Formula | C13H13ClN2O |
| Molecular Weight | 248.708 |
| Charge | 0 |
| Count |
|
| Stereochemistry | RACEMIC |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 1 |
| E/Z Centers | 0 |
| Optical Activity | ( + / - ) |
Selisistat (EX 527) was discovered by Elixir scientists as a selective human SIRT1 inhibitor and exhibits >200-fold selectivity against SIRT2 and SIRT3. Human SIRT1 is an enzyme that deacetylates the p53 tumor suppressor protein and has been suggested to modulate p53-dependent functions including DNA damage-induced cell death. It was shown that drug was highly safe in toxicology studies. Selisistat passed Phase II clinical trials to treat Huntington’s disease, but that study was discontinued.
Approval Year
Doses
| Dose | Population | Adverse events |
|---|---|---|
600 mg single, oral Highest studied dose Dose: 600 mg Route: oral Route: single Dose: 600 mg Sources: Page: p.483 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: FASTED Population Size: 6 Sources: Page: p.483 |
|
300 mg 1 times / day multiple, oral Studied dose Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.483 |
healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: FASTED Population Size: 6 Sources: Page: p.483 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. | 2005 Dec 15 |
|
| Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. | 2006 Jan |
|
| N(epsilon)-thioacetyl-lysine-containing tri-, tetra-, and pentapeptides as SIRT1 and SIRT2 inhibitors. | 2009 Apr 9 |
|
| Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. | 2010 May |
|
| Resveratrol prevents RANKL-induced osteoclast differentiation of murine osteoclast progenitor RAW 264.7 cells through inhibition of ROS production. | 2010 Oct 22 |
|
| Acetylation of tau inhibits its degradation and contributes to tauopathy. | 2010 Sep 23 |
|
| Resveratrol potentiates glucose-stimulated insulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependent mechanism. | 2011 Feb 25 |
|
| Sirt1 overexpression protects murine osteoblasts against TNF-α-induced injury in vitro by suppressing the NF-κB signaling pathway. | 2012 May |
|
| Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. | 2013 Dec 20 |
|
| Resveratrol differentially regulates NAMPT and SIRT1 in Hepatocarcinoma cells and primary human hepatocytes. | 2014 |
|
| Des-acyl ghrelin protects microvascular endothelial cells from oxidative stress-induced apoptosis through sirtuin 1 signaling pathway. | 2014 Apr |
|
| Sesamin ameliorates doxorubicin-induced cardiotoxicity: involvement of Sirt1 and Mn-SOD pathway. | 2014 Jan 13 |
|
| Non-specific SIRT inhibition as a mechanism for the cytotoxicity of ginkgolic acids and urushiols. | 2014 Sep 2 |
|
| Resveratrol via sirtuin-1 downregulates RE1-silencing transcription factor (REST) expression preventing PCB-95-induced neuronal cell death. | 2015 Nov 1 |
Sample Use Guides
100 mg, immediate release tablets, once daily administration. Subjects in the Fasted group will take study drug after an overnight fast (since at least midnight).
Route of Administration:
Oral
It was used EX-527 (selisistat) to examine the role of SIRT1 in p53 acetylation and cell survival after DNA damage. Treatment with EX-527 dramatically increased acetylation at lysine 382 of p53 after different types of DNA damage in primary human mammary epithelial cells and several cell lines. Significantly, inhibition of SIRT1 catalytic activity by EX-527 had no effect on cell growth, viability, or p53-controlled gene expression in cells treated with etoposide. Acetyl-p53 was also increased by the histone deacetylase (HDAC) class I/II inhibitor trichostatin A (TSA). EX-527 and TSA acted synergistically to increase acetyl-p53 levels, confirming that p53 acetylation is regulated by both SIRT1 and HDACs. While TSA alone reduced cell survival after DNA damage, the combination of EX-527 and TSA had no further effect on cell viability and growth. The deacetylation assay was performed with approximately 30 ng of GST-SIRT1 in the presence of EX-527 (48 pM to 100 μM). To determine the effects of deacetylase inhibitors on p53 acetylation levels, cells were treated with 6.25 to 400 nM TSA and/or 1 μM EX-527.
| Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 17:07:52 GMT 2023
by
admin
on
Sat Dec 16 17:07:52 GMT 2023
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| Record UNII |
L19ECD5014
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| Record Status |
Validated (UNII)
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| Record Version |
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Common Name | English |
| Classification Tree | Code System | Code | ||
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EU-Orphan Drug |
EU/3/09/681
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NCI_THESAURUS |
C1509
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FDA ORPHAN DRUG |
295709
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DB13978
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