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CC-3052: A Water-Soluble Analog of Thalidomide and Potent Inhibitor of Activation-Induced TNF- Production¹

J. Blake Marriott^2,*, Michael Westby^3,*, Sharon Cookson^*, Mary Guckian^*, Steve Goodbourn, George Muller, Mary G. Shire, David Stirling and Angus G. Dalgleish^*

Divisions of ^* Oncology and Biochemistry, Department of Cellular and Molecular Sciences, St George’s Hospital Medical School, Cranmer Terrace, London, United Kingdom; and Celgene Corporation, Warren, NJ 07059

The immunomodulatory drug thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF- synthesis. However, its use is restricted by potentially serious side effects, including teratogenicity and neuorotoxicity; furthermore, insolubility may present problems in terms of systemic bioavailability. Recently, structural modifications of thalidomide have been designed enabling greatly enhanced anti-TNF- activity in LPS-treated mice. In contrast to thalidomide (LPS-induced TNF- IC₅₀ 200 µM in DMSO) and other analogs tested, one of these compounds, CC-3052 (IC₅₀ 1 µM in water), is water soluble. Furthermore, this analog exhibits increased stability in human plasma (t_1/2 17.5 vs 1.5 h for thalidomide) and appears to be nontoxic, nonmutagenic, and nonteratogenic. At pharmacologically active levels, cellular proliferation and LPS-induced IL-6 mRNA and IL-12p40 mRNA (as well as IL-1ß and IL-6 protein levels) in whole blood cultures were not affected; apparent inhibition of NK activity by CC-3052 was reversed upon addition of exogenous rTNF-. In addition, IL-10 mRNA and protein levels were increased. These properties are consistent with results indicating inhibition of phosphodiesterase type IV activity by CC-3052. Furthermore, CC-3052 did not increase the degradation rate of macrophage TNF- transcripts nor inhibit LPS-induced primary macrophage NF-B activation. Taken together, the potency of selective TNF- inhibition, water solubility, and increased plasma stability make CC-3052 an excellent candidate for further development and clinical evaluation for the treatment of TNF--mediated disease.

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