TY - JOUR
T1 - Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor
AU - Mbalaviele, Gabriel
AU - Pauley, Adele M.
AU - Shaffer, Alexander F.
AU - Zweifel, Ben S.
AU - Mathialagan, Sumathy
AU - Mnich, Stephen J.
AU - Nemirovskiy, Olga V.
AU - Carter, Jeff
AU - Gierse, James K.
AU - Wang, Jane L.
AU - Vazquez, Michael L.
AU - Moore, William M.
AU - Masferrer, Jaime L.
PY - 2010/5/15
Y1 - 2010/5/15
N2 - Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE2 synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC50 = 16.5 ± 3.8 nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE2 synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE2 synthesis (IC50 in the range of 0.5-5 μM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF1α (PGF1α) and PGF2α. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE2, PGF1α and PGF2α synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.
AB - Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E2 (PGE2) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE2 synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC50 = 16.5 ± 3.8 nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE2 synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE2 synthesis (IC50 in the range of 0.5-5 μM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF1α (PGF1α) and PGF2α. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE2, PGF1α and PGF2α synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.
KW - Arthritis
KW - Cyclooxygenase-2
KW - Inflammation
KW - Prostaglandins
KW - mPGES-1
UR - http://www.scopus.com/inward/record.url?scp=77649189835&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2010.01.003
DO - 10.1016/j.bcp.2010.01.003
M3 - Article
C2 - 20067770
AN - SCOPUS:77649189835
SN - 0006-2952
VL - 79
SP - 1445
EP - 1454
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 10
ER -