In:
PLOS ONE, Public Library of Science (PLoS), Vol. 19, No. 6 ( 2024-6-24), p. e0305000-
Abstract:
Human sirtuin-2 (SIRT2) has emerged as an attractive drug target for a variety of diseases. The enzyme is a deacylase that can remove chemically different acyl modifications from protein lysine residues. Here, we developed a high-throughput screen based on a homogeneous time-resolved fluorescence (HTRF) binding assay to identify inhibitors of SIRT2’s demyristoylase activity, which is uncommon among many ligands that only affect its deacetylase activity. From a test screen of 9600 compounds, we identified a small molecule that inhibited SIRT2’s deacetylase activity (IC 50 = 7 μM) as well as its demyristoylase activity (IC 50 = 37 μM). The inhibitor was composed of two small fragments that independently inhibited SIRT2: a halogenated phenol fragment inhibited its deacetylase activity, and a tricyclic thiazolobenzimidazole fragment inhibited its demyristoylase activity. The high-throughput screen also detected multiple deacetylase-specific SIRT2 inhibitors.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0305000
DOI:
10.1371/journal.pone.0305000.g001
DOI:
10.1371/journal.pone.0305000.g002
DOI:
10.1371/journal.pone.0305000.g003
DOI:
10.1371/journal.pone.0305000.g004
DOI:
10.1371/journal.pone.0305000.g005
DOI:
10.1371/journal.pone.0305000.g006
DOI:
10.1371/journal.pone.0305000.s001
DOI:
10.1371/journal.pone.0305000.s002
DOI:
10.1371/journal.pone.0305000.s003
DOI:
10.1371/journal.pone.0305000.s004
DOI:
10.1371/journal.pone.0305000.s005
DOI:
10.1371/journal.pone.0305000.s006
DOI:
10.1371/journal.pone.0305000.s007
DOI:
10.1371/journal.pone.0305000.s008
DOI:
10.1371/journal.pone.0305000.s009
DOI:
10.1371/journal.pone.0305000.s010
DOI:
10.1371/journal.pone.0305000.s011
DOI:
10.1371/journal.pone.0305000.s012
DOI:
10.1371/journal.pone.0305000.s013
DOI:
10.1371/journal.pone.0305000.r001
DOI:
10.1371/journal.pone.0305000.r002
DOI:
10.1371/journal.pone.0305000.r003
DOI:
10.1371/journal.pone.0305000.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2024
detail.hit.zdb_id:
2267670-3
Permalink