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Immunomodulatory Drug CC-4047 is a Cell-type and Stimulus-Selective Transcriptional Inhibitor of Cyclooxygenase 2

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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® 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-1β 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.

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ACKNOWLEDGMENTS

We thank members of the Discovery Research and Biology programs at Celgene for helpful discussions and critical review of the data contained in this manuscript.

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Authors and Affiliations

  1. Celgene Corporation, 4550 Towne Center Court, San Diego, CA, 92121, USA

    Gregory D. Ferguson, Kristen Jensen-Pergakes, Candice Wilkey, Urvi Jhaveri, Normand Richard, Dominique Verhelle, Laure Moutouh De Parseval, Laura G. Corral, Weilin Xie, Helen Brady & Kyle Chan

  2. Loma Linda University Medical Center, Department of Pediatrics, Loma Linda, CA, 92354, USA

    Christopher L. Morris

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  1. Gregory D. Ferguson
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Correspondence to Gregory D. Ferguson.

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Ferguson, G.D., Jensen-Pergakes, K., Wilkey, C. et al. Immunomodulatory Drug CC-4047 is a Cell-type and Stimulus-Selective Transcriptional Inhibitor of Cyclooxygenase 2. J Clin Immunol 27, 210–220 (2007). https://doi.org/10.1007/s10875-007-9070-6

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