PMID- 27431267
OWN - NLM
STAT- MEDLINE
DCOM- 20180710
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 6
DP  - 2016 Jul 19
TI  - Comparative chemical array screening for p38gamma/delta MAPK inhibitors using a single 
      gatekeeper residue difference between p38alpha/beta and p38gamma/delta.
PG  - 29881
LID - 10.1038/srep29881 [doi]
LID - 29881
AB  - Mammalian p38 mitogen activated protein kinases (MAPKs) are responsive to a 
      variety of cellular stresses. The development of specific pyridinyl imidazole 
      inhibitors has permitted the characterization of the p38 MAPK isoform p38alpha, which 
      is expressed in most cell types, whereas the physiological roles of p38gamma and p38delta 
      are poorly understood. In this study, we report an approach for identifying 
      selective inhibitors against p38gamma and p38delta by focusing on the difference in 
      gatekeeper residues between p38alpha/beta and p38gamma/delta. Using GST-fused p38alpha wild type and 
      T106M mutant constructs, wherein the p38alpha gatekeeper residue (Thr-106) was 
      substituted by the p38gamma/delta-type (Met), we performed comparative chemical array 
      screening to identify specific binders of the mutant and identified SU-002 bound 
      to p38alphaT106M specifically. SU-002 was found to inhibit p38alphaT106M but not p38alpha 
      kinase activity in in vitro kinase assays. SU-005, the analog of SU-002, had 
      inhibitory effects against the kinase activity of p38gamma and p38delta in vitro but not 
      p38alpha. In addition, SU-005 inhibited both p38gamma and p38delta auto-phosphorylation in 
      HeLa and HEK293T cells. These results demonstrate that the comparative chemical 
      array screening approach is a powerful technique to explore specific inhibitors 
      for mutant proteins with even single amino-acid substitutions in a 
      high-throughput manner.
FAU - Kondoh, Yasumitsu
AU  - Kondoh Y
AD  - Antibiotics Laboratory, RIKEN, Saitama 351-0198, Japan.
AD  - Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 
      Saitama 351-0198, Japan.
FAU - Honda, Kaori
AU  - Honda K
AD  - Bio-Active Compounds Discovery Research Unit, RIKEN Center for Sustainable 
      Resource Science, Saitama 351-0198, Japan.
FAU - Hiranuma, Sayoko
AU  - Hiranuma S
AD  - Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 
      Saitama 351-0198, Japan.
FAU - Hayashi, Teruo
AU  - Hayashi T
AD  - Antibiotics Laboratory, RIKEN, Saitama 351-0198, Japan.
FAU - Shimizu, Takeshi
AU  - Shimizu T
AD  - Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 
      Saitama 351-0198, Japan.
FAU - Watanabe, Nobumoto
AU  - Watanabe N
AD  - Bio-Active Compounds Discovery Research Unit, RIKEN Center for Sustainable 
      Resource Science, Saitama 351-0198, Japan.
FAU - Osada, Hiroyuki
AU  - Osada H
AD  - Antibiotics Laboratory, RIKEN, Saitama 351-0198, Japan.
AD  - Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 
      Saitama 351-0198, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160719
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Imidazoles)
RN  - 0 (Protein Isoforms)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 7GBN705NH1 (imidazole)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - *Drug Evaluation, Preclinical
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Imidazoles/chemistry/pharmacology
MH  - Phosphorylation
MH  - Protein Isoforms/*antagonists & inhibitors/genetics
MH  - Protein Kinase Inhibitors/chemistry/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/*antagonists & inhibitors/genetics
PMC - PMC4949465
EDAT- 2016/07/20 06:00
MHDA- 2018/07/11 06:00
PMCR- 2016/07/19
CRDT- 2016/07/20 06:00
PHST- 2016/02/18 00:00 [received]
PHST- 2016/06/23 00:00 [accepted]
PHST- 2016/07/20 06:00 [entrez]
PHST- 2016/07/20 06:00 [pubmed]
PHST- 2018/07/11 06:00 [medline]
PHST- 2016/07/19 00:00 [pmc-release]
AID - srep29881 [pii]
AID - 10.1038/srep29881 [doi]
PST - epublish
SO  - Sci Rep. 2016 Jul 19;6:29881. doi: 10.1038/srep29881.