Back to Search
Start Over
Identification of Diketopiperazine-Containing 2-Anilinobenzamides as Potent Sirtuin 2 (SIRT2)-Selective Inhibitors Targeting the 'Selectivity Pocket', Substrate-Binding Site, and NAD+-Binding Site
- Source :
- Journal of Medicinal Chemistry. 62:5844-5862
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- The NAD+-dependent deacetylase SIRT2 represents an attractive target for drug development. Here, we designed and synthesized drug-like SIRT2-selective inhibitors based on an analysis of the putative binding modes of recently reported SIRT2-selective inhibitors and evaluated their SIRT2-inhibitory activity. This led us to develop a more drug-like diketopiperazine structure as a "hydrogen bond (H-bond) hunter" to target the substrate-binding site of SIRT2. Thioamide 53, a conjugate of diketopiperazine and 2-anilinobenzamide which is expected to occupy the "selectivity pocket" of SIRT2, exhibited potent SIRT2-selective inhibition. Inhibition of SIRT2 by 53 was mediated by the formation of a 53-ADP-ribose conjugate, suggesting that 53 is a mechanism-based inhibitor targeting the "selectivity pocket", substrate-binding site, and NAD+-binding site. Furthermore, 53 showed potent antiproliferative activity toward breast cancer cells and promoted neurite outgrowth of Neuro-2a cells. These findings should pave the way for the discovery of novel therapeutic agents for cancer and neurological disorders.
- Subjects :
- Protein Conformation
Stereochemistry
Diketopiperazines
SIRT2
01 natural sciences
Substrate Specificity
Structure-Activity Relationship
03 medical and health sciences
Sirtuin 2
Sirtuin 1
Drug Discovery
Humans
Enzyme Inhibitors
Binding site
Thioamide
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
biology
NAD
0104 chemical sciences
Molecular Docking Simulation
NAD binding
010404 medicinal & biomolecular chemistry
chemistry
Benzamides
Sirtuin
MCF-7 Cells
biology.protein
Molecular Medicine
NAD+ kinase
Selectivity
Conjugate
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....78c01dda38ae4c933afd89964def8a87