We are seeking to optimize and develop small molecule modulators of the protein PDI as a treatment for AD. PDI abundance is increased in the presence of misfolded proteins, resulting in accumulation of damaging reactive oxygen species (ROS), which are a byproduct of the PDI catalytic cycle of reducing, oxidizing and isomerizing disulfide-containing substrates. Small molecule modulators of PDI have the potential to suppress the excess ROS that accumulate in protein misfolding diseases such as AD. We have discovered a drug-like, brain-penetrant small molecule, termed LOC14, which is capable of oxidizing PDI, protecting cells and brain slice cultures from the stress of protein misfolding, and benefiting HD model mice, another protein misfolding disease. In the previous year, we discovered several key improvements in this scaffold, and evaluated its suitability using a variety of drug development assays. Our goal in the proposed research project for the next year is to evaluate the PK/PD properties of the best compounds we have identified, make further chemical modifications if needed, definition the mechanism of action of this compound series in more detail, and select PD and predictive biomarkers that will both report on exposure to the compounds in mice and humans, and predict which patients and models are most likely to respond to these compounds. Together, we believe these experiments will constitute a pivotal step, by providing a drug-like, optimized development candidate that is suitable for further pre-clinical and clinical evaluation as the first in class of a new class of therapeutic agents for AD.