The Prostaglandin Transporter: Eicosanoid Reuptake, Control of Signaling, and Development of High-Affinity Inhibitors as Drug Candidates.
We discovered the prostaglandin transporter (PGT) and cloned the human cDNA and gene. PGT transports extracellular prostaglandins (PGs) into the cytoplasm for enzymatic inactivation. PGT knockout mice have elevated prostaglandin E2 (PGE2) and neonatal patent ductus arteriosus, which reflects PGT's control over PGE2 signaling at EP1/EP4 cell-surface receptors. Interestingly, rescued PGT knockout pups have a nearly normal phenotype, as do human PGT nulls. Given the benign phenotype of PGT genetic nulls, and because PGs are useful medicines, we have approached PGT as a drug target. Triazine library screening yielded a lead compound of inhibitory constant 50% (IC50) = 3.7 μM, which we developed into a better inhibitor of IC50 378 nM. Further structural improvements have yielded 26 rationally designed derivatives with IC50 < 100 nM. The therapeutic approach of increasing endogenous PGs by inhibiting PGT offers promise in diseases such as pulmonary hypertension and obesity.
Bronx, NY.
Victor L
VL
Schuster
Bronx, NY.
Yuling
Y
Chi
Bronx, NY.
Run
R
Lu
D000818:Animals; D001692:Biological Transport; D004285:Dogs; D015195:Drug Design; D015777:Eicosanoids / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008822:Mice, Transgenic; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014162:Transfection; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D015777:Eicosanoids; D027361:Organic Anion Transporters; C503526:SLCO2A1 protein, human; C503527:Slco2a1 protein, mouse; C503528:Slco2a1 protein, rat; D014227:Triazines