Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor

Gabriel Mbalaviele, Adele M. Pauley, Alexander F. Shaffer, Ben S. Zweifel, Sumathy Mathialagan, Stephen J. Mnich, Olga V. Nemirovskiy, Jeff Carter, James K. Gierse, Jane L. Wang, Michael L. Vazquez, William M. Moore, Jaime L. Masferrer

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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-PGF (PGF) and PGF. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE2, PGF and PGF synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.

Original languageEnglish
Pages (from-to)1445-1454
Number of pages10
JournalBiochemical Pharmacology
Volume79
Issue number10
DOIs
StatePublished - May 15 2010

Keywords

  • Arthritis
  • Cyclooxygenase-2
  • Inflammation
  • Prostaglandins
  • mPGES-1

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