Design, synthesis, and biological evaluation of halogenated N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: discovery of an isoform-selective small molecule phospholipase D2 inhibitor.
Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD1 and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (>1700-fold selective), and moderately PLD2-preferring (>10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date, N-(2-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.
Lavieri
Robert R
RR
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600, USA.
Scott
Sarah A
SA
Selvy
Paige E
PE
Kim
Kwangho
K
Jadhav
Satyawan
S
Morrison
Ryan D
RD
Daniels
J Scott
JS
Brown
H Alex
HA
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010739:Phospholipase D / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001798:Blood Proteins; D007527:Isoenzymes; C552712:N-(2-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro(4.5)decan-8-yl)ethyl)-2-naphthamide; D009281:Naphthalenes; D013141:Spiro Compounds; C105606:phospholipase D2; D010739:Phospholipase D