Development of PDE5 Inhibitors for Localized Delivery to Prevent Colorectal Cancer

点击翻译按钮获取中文摘要

PROJECT SUMMARY Cancer of the colorectum (CRC) is one of the most common cancers in the world, representing about 8% of all annually reported cancers. Chemoprevention of CRC development is, therefore, a priority for people at high risk, though no drugs are currently available for this unmet clinical need. This work is aimed at developing PDE5 inhibitors (PDE5i) for colon cancer prevention. Novel PDE5i will show fewer side effects than existing PDE5i by designing their polar structural analogs to affect the gut lining while minimizing entrance into the bloodstream. Our strategy is to design novel localized PDE5i’s that remain in the GI tract to specifically target GI diseases. As proof of principle, we have synthesized and tested 2 novel polar analogs of sildenafil: malonyl sildenafil and boronyl-sildenafil. Our central hypothesis is to develop and test new gut localized analogs of sildenafil that have been proven to be effective in colon cancer prevention in preclinical models. Our long-term goal is to develop a family of gut-localized, safe, and effective drugs that can be used for colon cancer prevention. The objective of this proposal is to develop a library of structurally optimized novel chemical entities and determine their efficacy at inhibiting PDE5i in vitro and in mice. The research approaches used in this project will be implemented in the existing Medicinal Chemistry undergraduate program at Augusta University. This project blends the expertise of medicinal chemistry and biology and their roles in early drug discovery. Both the drug design and biological testing reflect the key steps in the pharmaceutical industry workflow for drug development. We will test our hypothesis in this research project by pursuing two specific aims: Specific Aim 1: Develop novel polar analogs of sildenafil for localized delivery and inhibition of PDE5. Specific Aim 2: Develop and test a formulation for the targeted delivery of novel drug candidates. This project is highly innovative and educational in that it merges chemistry and biology during the drug discovery process. This approach corresponds to the student learning outcomes of the Rational Drug Design course, Medicinal Chemistry course, and undergraduate research student courses. This research project will also promote student interest in the master’s program, which offers a Master’s of Science degree in Biomolecular Science. Successful completion of this program will promote drug discovery undergraduate research and result in developing novel drug candidates for colon cancer prevention. Our project outcomes will change the methods, treatments, services, or preventative interventions for patients predisposed to CRC by providing a daily chemoprevention drug as an additional option to the chemoprevention of CRC besides colonoscopies.