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Ashley Diaz

Ashley Diaz

Ashley Diaz, a senior neuroscience and chemistry double major at Emory University, used organic chemistry to improve drug-like properties in a potential therapeutic for Type 2 Diabetes.

BRD5653 is an organic compound that was found via phenotypic screening to selectively induce the secretion of insulin in the presence of glucose. The Broad has taught me that the true measure of a scientist is not how much one knows, but rather, how well one can communicate this knowledge with those outside of a particular discipline. This lesson in the importance of communication has been an essential part of my development as a researcher and would not have been possible without the incredible interdisciplinary environment of the Broad Institute.This mode of action has potential applications for the treatment of diabetes by eliminating the need for administration of insulin, which can be problematic if not dosed with effective glucose monitoring. In order to further develop this hit compound, drug-like properties must be optimized.

Our project is focused on improving the solubility of compound BRD5653 by modifying an aromatic portion of the molecule to increase the amount of sp3-hybridization. This method of increasing three-dimensionality of a molecule has shown to be effective in the past for increasing solubility. We accomplished this by designing and optimizing synthetic routes to afford several different versions of the compound that explore different ring architectures and geometries. These compounds were then profiled in a cell-based insulin secretion assay and a kinetic solubility assay. The compounds were found to exhibit better solubility while also maintaining activity. The synthesized compounds can undergo further in vitro profiling and in vivo studies. This work is not only informative for development of BRD5653 and diabetic research, but is also important to the medicinal chemistry community to compare the effect of different isosteres on solubility.

 

Project: Improving drug-like properties in a potential therapeutic for Type 2 Diabetes

Mentors: Brian Chamberlain and Florence Wagner, Center for the Development of Therapeutics (CDoT)