title: Immunomodulatory drug CC-4047 is a cell-type and stimulus-selective transcriptional inhibitor of cyclooxygenase 2.
abstract: COX2 (prostaglandin G/H synthase, PTGS2) is a well-validated target in the fields of both oncology and inflammation. Despite their significant toxicity profile, non-steroidal anti-inflammatory drugs (NSAIDs) have become standard of care in the treatment of many COX2-mediated inflammatory conditions. In this report, we show that one IMiDs((R)) immunomodulatory drug, CC-4047, can reduce the levels of COX2 and the production of prostaglandins (PG) in human LPS-stimulated monocytes. The inhibition of COX2 by CC-4047 occurs at the level of gene transcription, by reducing the LPS-stimulated transcriptional activity at the COX2 gene. Because it is a transcriptional rather than an enzymatic inhibitor of COX2, CC-4047 inhibition of PG production is not susceptible to competition by exogenous arachadonic acid (AA). The distinct mechanisms of action allow CC-4047 and a COX2-selective NSAID to work additively to block PG secretion from monocytes. CC-4047 does not, however, block COX2 induction in or prostacyclin secretion from IL-1beta stimulated human umbilical vein endothelial cells (HUVEC) cells, nor does it inhibit COX1 in either monocytes or HUVEC cells. CC-4047 also inhibits COX2 and PG production in monocytes derived from patients with sickle cell disease (SCD). Taken together, the data in this manuscript suggest CC-4047 will provide important anti-inflammatory benefit to patients and will improve the safety of NSAIDs in the treatment of SCD or other inflammatory conditions.
authors.affiliation: Celgene Corporation, 4550 Towne Center Court, San Diego, CA 92121, USA. gferguson@celgene.com
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Ferguson
authors.forename: Kristen
authors.initials: K
authors.lastname: Jensen-Pergakes
authors.forename: Candice
authors.initials: C
authors.lastname: Wilkey
authors.forename: Urvi
authors.initials: U
authors.lastname: Jhaveri
authors.forename: Normand
authors.initials: N
authors.lastname: Richard
authors.forename: Dominique
authors.initials: D
authors.lastname: Verhelle
authors.forename: Laure Moutouh
authors.initials: LM
authors.lastname: De Parseval
authors.forename: Laura G
authors.initials: LG
authors.lastname: Corral
authors.forename: Weilin
authors.initials: W
authors.lastname: Xie
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morris
authors.forename: Helen
authors.initials: H
authors.lastname: Brady
authors.forename: Kyle
authors.initials: K
authors.lastname: Chan
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013792:Thalidomide; C467566:pomalidomide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human