Antiproliferative effect of CHR-2797, a novel aminopeptidase inhibitor, in the human breast cancer xenograft, MDA-MB 435

637 The aminopeptidase inhibitor CHR-2797 is currently in Phase I clinical evaluation for the treatment of advanced malignancies CHR-2797 is a novel orally active metallo-enzyme inhibitor with pleiotropic activity against a range of human cancers. A substantial body of evidence indicates that the molecular targets underpinning these pleiotropic effects are intracellular aminopeptidases. Both CHR-2797 and an active metabolite, CHR-79888, are pharmacologically active and may exert their anti-proliferative effect by disruption of the turnover of cell cycle intermediates. CHR-2797 shows selective anti-proliferative activity against transformed cells over normal cells. The human breast carcinoma cell line, MDA-MB 435 was used for testing the activity of CHR-2797 in a murine xenograft model. Tumors were inoculated intravenously in female nude mice (18 animals per group) via the tail vein (day 0) and subsequently localized to the lungs. Oral dosing with 100 mg/kg/day commenced on day 2 after cell inoculation and continued throughout the experiment. Compared to vehicle, CHR-2797 significantly inhibited lung tumor burden by 98% (p