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Research Articles: Therapeutics

CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo

Celera Genomics, South San Francisco, California

Requests for reprints: Joseph J. Buggy, Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080. Phone: 650-866-6236; Fax: 650-866-6652. E-mail: drjbuggy{at}yahoo.com

CRA-024781 is a novel, broad spectrum hydroxamic acid–based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a K_i of 0.007 µmol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of -tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity. [Mol Cancer Ther 2006;5(5):1309–17]

Received 10/25/05; revised 2/ 6/06; accepted 3/ 2/06.