Synthesis and antitumor activity of an inhibitor of fatty acid synthase

Compared to normal human tissues, many common human cancers, including carc inoma of the colon, prostate, ovary, breast, and endometrium, express high levels of fatty acid synthase (FAS, EC 2.3.1.85), the primary enzyme respon sible for the synthesis of fatty acids. This differential expression of FAS between normal tissues and cancer has led to the notion that FAS is a targ et for anticancer drug development. Recent studies with C75, an inhibitor o f fatty acid synthesis, have shown significant antitumor activity with conc omitant inhibition of fatty acid synthesis in tumor tissue and normal liver . importantly, histopathological analysis of normal tissues after C75 treat ment showed no adverse effects on proliferating cellular compartments. such as bone marrow, gastrointestinal tract, skin, or lymphoid tissues. In this study, we describe the de novo synthesis of C75 based on the known mechani sm of action of cerulenin and the theoretical reaction intermediates of the beta-ketoacyl synthase moiety of FAS. In addition, we demonstrate that C75 is a synthetic, chemically stable inhibitor of FAS. C75 inhibits purified mammalian FAS with characteristics of a slow-binding inhibitor and also inh ibits fatty acid synthesis in human cancer cells. Treatment of human breast cancer cells with [5(3)H]C75 demonstrates that C75 reacts preferentially w ith FAS in whole cells. Therefore, we have shown that the primary mechanism of the antitumor activity of C75 is likely mediated through its interactio n with, and inhibition of, FAS. This development will enable the in vivo st udy of FAS inhibition in human cancer and other metabolic diseases.