Angiogenesis, the recruitment of new blood vessels, is recognized as an important factor in tumor proliferation in many types of cancer. It is generally accepted that therapeutic approaches that inhibit angiogenesis effectively limit, or even prevent, the formation of solid tumors. It has also been shown that anti-angiogenic therapeutics allow conventional radiation therapy and chemotherapy to be more effective.
This invention pertains to certain compounds that inhibit angiogenesis in a previously unrecognized way. These compounds also inhibit the proliferation of cells within intraepithelial neoplasias (clusters of abnormally proliferating epithelial cells that are the origin of cancers). The subject compounds specifically block the formation of the amino acids hypusine and hydroxyproline. The former is the critical residue of eukaryotic translation initiation factor 5A (eIF5A), which is important in cell cycle progression, and hydroxyproline constitutes the critical residue of the collagens. The targeted enzymes are deoxyhypusine hydroxylase and prolyl 4-hydroxylase, respectively.
This invention provides evidence for an important role of eIF-5A in angiogenesis, and discloses a family of compounds with useful clinical properties. Specifically, these compounds include the core structures and potential derivatives of ciclopirox olamine, deferiprone, deferoxamine, and 2,2'-dipyridyl.
Ciclopirox olamine has potential for treatment of oral-pharyngeal cancer, and chemoprevention and treatment of cervical and vulvar cancer. Notably, this drug is FDA-approved in the USA as a topical medication against fungal infections while, in Europe, it is also approved for the treatment of yeast infections of the genital tract. The compound has a known clinical profile and lacks teratogenicity, potentially expediting clinical trials for new cancer treatment indications.