Towards the goal of developing a treatment for ovarian cancer that utilizes a new mechanism of action, we are proposing to make analogues of (5Z)-7-oxozeaenol, a resorcylic acid lactone, that inhibits TAK1. Instead of synthesizing analogues de novo, the natural product will be isolated since it is available in sufficient quantities (>500 mg per 1 L fermentation flask) and already has the requisite molecular complexity to imbue potent activity (IC50 = 8.1 nM). Preliminary data has been acquired for over 30 compounds, a suite of synthesized and isolated compounds, and their TAK1 inhibition activities have been determined. The most potent analogue was a non-aromatic difluorinated compound, the first non-aromatic resorcylic acid lactone to have a reported TAK1 inhibition. These data were recently published and a patent filed to protect these compounds for future efforts. Building off these data, we have assembled a team, led by synthetic chemistry (Croatt, PI), to use the isolated natural product (Oberlies and Pearce) as the starting material and build in the structural modifications (Runyon) that the crystal structure suggests will lead to improved activity (Burdette). These compounds will be analyzed for TAK1 inhibition, and compounds with sufficient potency will be studied for their stability and solubility properties, kinase selectivity, and activity in in vitro ovarian cancer cell lines that have increased levels of TAK1 (Burdette). The medicinal chemistry consultant (Runyon) will meet quarterly with the team to suggest modifications and areas to explore or avoid. Not only will this be significant to the study of ovarian cancer, but the students trained on this project will also benefit from the breadth of study. Illustrative of this training, the student in the Croatt lab that acquired the majority of the preliminary data for this grant obtained experience in personally running many reactions, NMRs, HPLCs, UPLCs, Mass Specs, and computational chemistry experiments. The breadth of her experience, and recent publication, placed her in a great position for her future career in academia. Similar to the experiences of this student, and within the guise of an AREA grant (R15), the PI and other members of the team have a strong history of training students.
Ovarian cancer is the most lethal gynecological malignancy that kills approximately 14,000 people annually in the United States. For this proposal we are making novel compounds to study a new mechanism for the treatment of ovarian cancer. To optimally do so, we have assembled a team of synthetic, natural products, and medicinal chemists to work together towards this goal.
