2. Academic Validation
  3. α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands

α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands

  • J Med Chem. 2018 Jul 26;61(14):6261-6276. doi: 10.1021/acs.jmedchem.8b00661.
Jihyae Ann 1,  Agnes Czikora 2,  Amandeep S Saini 2,  Xiaoling Zhou 2,  Gary A Mitchell 2,  Nancy E Lewin 2,  Megan L Peach 3,  Peter M Blumberg 2,  Jeewoo Lee 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, College of Pharmacy , Seoul National University , Seoul 08826 , Republic of Korea.
  • 2 Laboratory of Cancer Biology and Genetics , Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , Maryland 20892 , United States.
  • 3 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.
PMID: 29860841 DOI: 10.1021/acs.jmedchem.8b00661
Abstract

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 PKCα and 45-fold selectivity relative to PKCε 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 PKCδ S299 phosphorylation, a measure of PKCδ stimulation.

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