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

  1. Author:
    Ann, Jihyae
    Czikora, Agnes
    Saini, Amandeep S.
    Zhou, Xiaoling
    Mitchell, Gary A.
    Lewin, Nancy E.
    Peach, Megan
    Blumberg, Peter M.
    Lee, Jeewoo

  2. Author Address

    Seoul Natl Univ, Coll Pharm, Lab Med Chem, Seoul 08826, South Korea.NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NIH, Basic Sci Program, Leidos Biomed Res Inc, Chem Biol Lab,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.
    1. Year: 2018
    2. Date: Jul 26
  2. Journal: Journal of Medicinal Chemistry
  3. AMER CHEMICAL SOC,
    1. 61
    2. 14
    3. Pages: 6261-6276
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    Diacylglycerol-lactones have proven to be a powerful template for the design of potent ligands targeting CI 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 PKC alpha 45 and 45-fold selectivity relative to PKC epsilon 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 PKC delta S299 phosphorylation, a measure of PKC delta stimulation.

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External Sources

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  2. DOI: 10.1021/acs.jmedchem.8b00661
  3. PMID: 29860841
  4. View record in Web of Science®
  5. WOS: 000440521300030

Library Notes

  1. Fiscal Year: FY2017-2018
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