Discovery of Desketoraloxifene Analogues as Inhibitors of Mammalian, Pseudomonas Aeruginosa, and NAPE Phospholipase D Enzymes

ACS Chem Biol. 2015 Feb 20;10(2):421-32. doi: 10.1021/cb500828m. Epub 2014 Nov 19.


Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection, and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes, small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues, additional parallel synthesis, and evaluation in multiple PLD assays, we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Molecular Structure
  • Phospholipase D / antagonists & inhibitors*
  • Phospholipase D / genetics
  • Phospholipase D / metabolism
  • Pseudomonas aeruginosa / enzymology*
  • Raloxifene Hydrochloride / analogs & derivatives*
  • Raloxifene Hydrochloride / chemistry
  • Raloxifene Hydrochloride / pharmacology*


  • Enzyme Inhibitors
  • Raloxifene Hydrochloride
  • Phospholipase D
  • NAPEPLD protein, human