Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes.
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.
Department of Pharmacology, ‡Department of Chemistry, §Department of Biochemistry, ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
Sarah A
SA
Scott
Cierra T
CT
Spencer
Matthew C
MC
O'Reilly
Kyle A
KA
Brown
Robert R
RR
Lavieri
Chul-Hee
CH
Cho
Dai-Il
DI
Jung
Richard C
RC
Larock
H Alex
HA
Brown
Craig W
CW
Lindsley
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D020849:Raloxifene Hydrochloride; D010739:Phospholipase D; C581518:NAPEPLD protein, human