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Bromodomain containing 4 (BRD4); IL-6

In vitro and rodent studies identified BRD4 inhibitors that could help treat inflammation. Fragment-based screening, chemical synthesis and in vitro testing of sulfonamide analogs of quinazolinone identified a lead compound as a nanomolar inhibitor of BRD4. In a human monocyte-based inflammation assay, the lead compound blocked lipopolysaccharide (LPS)-induced IL-6 production with a low micromolar EC50 value. In normal mice and rats, the lead compound showed oral bioavailability and good pharmacokinetics. Future studies could include testing the compound in animal models of inflammation.
Resverlogix Corp.'sRVX-208, an inhibitor of the bromodomain and extra terminal domain (BET) family of bromodomain-containing proteins including BRD4, is in Phase II testing to treat diabetes and atherosclerosis and Phase I testing to treat Alzheimer's disease (AD).
Mitsubishi Tanabe Pharma Corp. and Oncoethix S.A. have OTX015, a synthetic small molecule inhibitor of BET BRD2, BRD3 and BRD4, in Phase I testing to treat cancer.

SciBX 5(44); doi:10.1038/scibx.2012.1163
Published online Nov. 8, 2012

Patent and licensing status undisclosed

Fish, P. et al. J. Med. Chem.;
published online Oct. 25, 2012;
Contact: Dafydd R. Owen,
Pfizer Worldwide R&D, Cambridge, Mass.