CAREER: Modulating cell signaling and migration by targeted small-molecule binding to a key regulator of protein degradation

Controlled cell death is key to the removal of unheathy cells but new proteins are being discovered that contribute to the survival of unhealthy cells. The Smith Lab has designed small molecules that bind to a key protein involved in cell survival known as valosin-containing protein (VCP). This project seeks to modulate the function of VCP with small molecules to provide a fundamental understanding of the etiology of different diseases and provide clues to their future treatment.

This project will be incorporated into a summer bridge program aimed at introducing incoming freshmen to research at Bowie State University, a Historically Black College & University (HCBU). During the summer students will participate in lab rotations in the Smith and other collaborating labs in the Department of Natural Sciences at Bowie State. These research experiences will demonstrate the importance of structure-function in small molecule-protein interactions through chemical synthesis, bioinformatics, biochemistry, and molecular biology projects.

In addition to research, the summer bridge program will introduce students to college-level biology, chemistry, bioinformatics, and physics. Given the robust research proposed and the nurturing environment of HBCUs, students participating in this program will have the skills and confidence to succeed in STEM.

Valosin-containing protein is a hexameric ATPase which is key to protein degradation due to its role in the ubiquitin-proteasome system. Many downstream effects of VCP modulation have been identified including cell migration. However current small molecules that target the ATPase activity of VCP are unselective.

Allosteric binders have shown promise as alternatives to ATPase binders, however acquired resistance has been observed. The Smith Lab has identified small molecules which bind to VCP through molecular docking. These molecules have the potential to be tools to understand how VCP binding effects downstream processes such as cell migration through regulation of p53 and NF-KB. Ultimately this study will give new insight into the role of VCP in cellular malignancy.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.