CC-3052 - A WATER-SOLUBLE ANALOG OF THALIDOMIDE AND POTENT INHIBITOR OF ACTIVATION-INDUCED TNF-ALPHA PRODUCTION

The immunomodulatory drug thalidomide has been shown to be clinically useful in a number of situations due to its ability to inhibit TNF-alp ha synthesis. However, its use is restricted by potentially serious si de 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-alpha activity in LPS-treated mice . In contrast to thalidomide (LPS-induced TNF-alpha IC50 similar to 20 0 mu M in DMSO) and other analogs tested, one of these compounds, CC-3 052 (IC50 similar to 1 mu M in water), is water soluble. Furthermore, this analog exhibits increased stability in human plasma (t(1/2) simil ar to 17.5 vs 1.5 h far thalidamide) and appears to be nontoxic, nonmu tagenic, and nonteratogenic. At pharmacologically active levels, cellu lar proliferation and LPS-induced IL-6 mRNA and IL-12p40 mRNA (as well as IL-1 beta and IL-6 protein levels) in whole blood cultures were no t affected; apparent inhibition of NK activity by CC-3052 was reversed upon addition of exogenous rTNF-alpha. In addition, IL-10 mRNA and pr otein levels were increased. These properties are consistent with resu lts indicating inhibition of phosphodiesterase type IV activity by CC- 3052, Furthermore, CC-3052 did not increase the degradation rate of ma crophage TNF-alpha transcripts nor inhibit LPS-induced primary macroph age NF-kappa B activation. Taken together, the potency of selective TN F-alpha inhibition, water solubility, and increased plasma stability m ake CC-3052 an excellent candidate for further development and clinica l evaluation for the treatment of TNF-alpha-mediated disease.