Centanamycin (AS-I-145 or NSC 716970) is an indolecarboxamide synthesized by Professor Moses Lee’s group at Hope University (USA) as a less toxic achiral analog of CC-1065 and duocarmycin, a natural product that binds the A-T rich DNA minor groove and alkylates DNA. Following initial demonstrations of the antitumor activity of the compound, it was sent to the NCI’s Developmental Therapeutics Program for further testing. The NCI-60 cell line screen showed that centanamycin had potent cytotoxic activity, with an average GI50 of 34 nM. The compound was then tested in the hollow fiber assay, yielding a total score of 54 points, and efficiently killing six different cell lines.
Preliminary efficacy studies were accomplished in animal xenograft models of glioma (SF295), and lung (H522), breast (MDA-MB-435), and ovarian (OVCAR-3) cancers. Administration of centanamycin via an oral route produced significant antitumor effects in all of the models. Compared with other CC-1065 analogs, centanamycin appears to exert decreased liver and bone marrow toxicity, as indicated by in vitro assays and from the xenograft studies.
Centanamycin was subjected to pharmacokinetics studies on mice and rats. There was minimal urinary and fecal excretion of the agent within the first 24 hr and relatively low concentrations of the compound in tissues examined (lungs, kidneys, heart, spleen, brain). The compound was still detectable at low levels in the plasma for at least 8 hr, and in tissues for at least 24 hr after administration, regardless of the routes of administration (i.v., i.p., and p.o.). The highest levels of the compound were found in the gall bladder, small intestine, small intestine contents, large intestine contents and liver, regardless of route of administration.
Further pre-clinical studies are ongoing at the NCI, Bethesda, MD. Given its potent activity and acceptable toxicity, it is hoped that centanamycin will transition into human clinical trials in the near future.