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The Synthetic Compound CC-5079 Is a Potent Inhibitor of Tubulin Polymerization and Tumor Necrosis Factor- Production with Antitumor Activity

Divisions of ¹ Immunotherapeutics and ² Signal Research, Celgene Corp., Summit, New Jersey

Requests for reprints: Ling-Hua Zhang, Celgene Corp., 86 Morris Avenue, Summit, NJ 07901. Phone: 908-673-9000; Fax: 908-673-9001; E-mail: Lzhang{at}celgene.com.

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC₅₀ value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G₂-M phase, increased phosphorylation of G₂-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [³H]colchicine for binding to tubulin; however, it does not compete with [³H]paclitaxel (Taxol) or [³H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor- (TNF-) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC₅₀, 270 nmol/L). This inhibitory effect on TNF- production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy. (Cancer Res 2006; 66(2): 951-9)

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