PMID- 29860841
OWN - NLM
STAT- MEDLINE
DCOM- 20190624
LR  - 20201209
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 61
IP  - 14
DP  - 2018 Jul 26
TI  - alpha-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras 
      Guanine-Releasing Protein 3 (RasGRP3) Ligands.
PG  - 6261-6276
LID - 10.1021/acs.jmedchem.8b00661 [doi]
AB  - Diacylglycerol-lactones have proven to be a powerful template for the design of 
      potent ligands targeting C1 domains, the recognition motif for the cellular 
      second messenger diacylglycerol. A major objective has been to better understand 
      the structure activity relations distinguishing the seven families of signaling 
      proteins that contain such domains, of which the protein kinase C (PKC) and 
      RasGRP families are of particular interest. Here, we synthesize a series of aryl- 
      and alkyl-substituted diacylglycerol-lactones and probe their relative 
      selectivities for RasGRP3 versus PKC. Compound 96 showed 73-fold selectivity 
      relative to PKCalpha and 45-fold selectivity relative to PKCepsilon for in vitro binding 
      activity. Likewise, in intact cells, compound 96 induced Ras activation, a 
      downstream response to RasGRP stimulation, with 8-29 fold selectivity relative to 
      PKCdelta S299 phosphorylation, a measure of PKCdelta stimulation.
FAU - Ann, Jihyae
AU  - Ann J
AD  - Laboratory of Medicinal Chemistry, College of Pharmacy , Seoul National 
      University , Seoul 08826 , Republic of Korea.
FAU - Czikora, Agnes
AU  - Czikora A
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Saini, Amandeep S
AU  - Saini AS
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Zhou, Xiaoling
AU  - Zhou X
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Mitchell, Gary A
AU  - Mitchell GA
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Lewin, Nancy E
AU  - Lewin NE
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Peach, Megan L
AU  - Peach ML
AD  - Basic Science Program, Leidos Biomedical Research Inc., Chemical Biology 
      Laboratory , Frederick National Laboratory for Cancer Research, National 
      Institutes of Health , Frederick , Maryland 21702 , United States.
FAU - Blumberg, Peter M
AU  - Blumberg PM
AD  - Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National 
      Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , 
      United States.
FAU - Lee, Jeewoo
AU  - Lee J
AUID- ORCID: 0000-0002-7832-6719
AD  - Laboratory of Medicinal Chemistry, College of Pharmacy , Seoul National 
      University , Seoul 08826 , Republic of Korea.
LA  - eng
GR  - ZIA BC005270/BC/NCI NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20180703
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (1,2-diacylglycerol)
RN  - 0 (Diglycerides)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Lactones)
RN  - 0 (Ligands)
RN  - 0 (RASGRP3 protein, human)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.13 (Protein Kinase C-epsilon)
SB  - IM
MH  - Diglycerides/*chemistry
MH  - *Drug Design
MH  - Guanine Nucleotide Exchange Factors/chemistry/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Lactones/*chemistry/*metabolism
MH  - Ligands
MH  - Models, Molecular
MH  - Protein Domains
MH  - Protein Kinase C-alpha/metabolism
MH  - Protein Kinase C-epsilon/metabolism
MH  - Substrate Specificity
MH  - ras Guanine Nucleotide Exchange Factors
EDAT- 2018/06/05 06:00
MHDA- 2019/06/25 06:00
CRDT- 2018/06/05 06:00
PHST- 2018/06/05 06:00 [pubmed]
PHST- 2019/06/25 06:00 [medline]
PHST- 2018/06/05 06:00 [entrez]
AID - 10.1021/acs.jmedchem.8b00661 [doi]
PST - ppublish
SO  - J Med Chem. 2018 Jul 26;61(14):6261-6276. doi: 10.1021/acs.jmedchem.8b00661. Epub 
      2018 Jul 3.