Abstract
Abstract Diazonamide A is a natural product originally isolated from a marine organism. It potently induces G2/M cell cycle arrest. Its molecular mode of action is not fully understood but its potential as a cancer therapeutic is high. To streamline our diazonamide synthesis and to define a minimal pharmacophore, we prepared a series of truncated structures. Its simplified structure and shortened synthesis allowed for extensive structure activity relationship analyses. Several modifications markedly improved activity. Among them, JP2295 and JP2362 were studied in details. Both compounds were highly efficacious in a wide spectrum of tumors from different origin both in vitro and in vivo. They were >20 fold more potent than AB5, a closely related analog of the natural product, in a MIA Paca-2 pancreatic cancer xenograft model. At dose 10-fold higher than the efficacious dose, JP2295 or JP2362 did not cause any apparent toxicity. Three out of 7 mice were completely free of tumor even 6 months after the initial treatment. In the same model, taxanes, i.e. paclitaxel and docetaxel, and vinca alkaloids, i.e. vinorelbine, vinblastine, and vincristine, were either less efficacious or causing severe body-weight loss, even animal death. Similar effects were observed in other xenograft models. Safety studies were further carried out in NIH Swiss mice and Sprague Dawley rats with similar results. In summary, JP2295 and JP2362 demonstrated over 20-fold bigger therapeutic window than taxanes and vinca alkaloids in rodents. Such a large therapeutic window is unique for a small molecule anti-mitotic and suggests further development is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5423. doi:10.1158/1538-7445.AM2011-5423
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