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 |
|---|---|---|
| The Sir2 family of protein deacetylases. | 2004 |
|
| 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 |
|
| SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. | 2010 Apr |
|
| Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. | 2010 May |
|
| SIRT1 modulates expression of matrix metalloproteinases in human dermal fibroblasts. | 2010 Oct |
|
| Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. | 2010 Sep 1 |
|
| Acetylation of tau inhibits its degradation and contributes to tauopathy. | 2010 Sep 23 |
|
| SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. | 2011 Aug |
|
| Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: a potential role for atrogin-1 in smooth muscle. | 2012 Jan-Feb |
|
| Sirt1 overexpression protects murine osteoblasts against TNF-α-induced injury in vitro by suppressing the NF-κB signaling pathway. | 2012 May |
|
| Activation of SIRT1 protects pancreatic β-cells against palmitate-induced dysfunction. | 2012 Nov |
|
| Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. | 2013 |
|
| Resveratrol suppresses the STAT3 signaling pathway and inhibits proliferation of high glucose-exposed HepG2 cells partly through SIRT1. | 2013 Dec |
|
| Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. | 2013 Dec 20 |
|
| Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 protein-mediated modulation of p300 protein. | 2013 Feb 22 |
|
| Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. | 2013 Jan |
|
| Age-associated changes in gene expression and developmental competence of bovine oocytes, and a possible countermeasure against age-associated events. | 2013 Jul |
|
| Resveratrol protects HUVECs from oxidized-LDL induced oxidative damage by autophagy upregulation via the AMPK/SIRT1 pathway. | 2013 Jun |
|
| SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging. | 2013 May 1 |
|
| 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 |
|
| SIRT1 inhibition restores apoptotic sensitivity in p53-mutated human keratinocytes. | 2014 Jun 15 |
|
| 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 |
|
| BET Inhibition Upregulates SIRT1 and Alleviates Inflammatory Responses. | 2015 Sep 21 |
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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Official Name | English | ||
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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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