Thursday, May 22, 2025
5/22/2025
Red-light driven targeted degradation of cancer proteins - PROJECT SUMMARY Targeted protein degradation has emerged as a powerful method to manipulate proteins, both for mechanistic studies and therapeutic applications. By selectively degrading a protein of interest, these modalities provide an orthogonal way to alter protein function that is distinct from traditional pharmacological approaches, which typically inhibit enzymatic or binding activity. Most strategies for protein degradation use bifunctional molecules, such as proteolysis targeting chimeras (PROTACs) and molecular glues, which simultaneously engage a protein target and the native protein degradation machinery in the cell (e.g. ubiquitin ligases) to tag the target for destruction. The use of endogenous enzymes and pathways to facilitate targeted degradation was a transformative concept, but reliance on these systems can also be a limitation. For example, not all cell types express the same ubiquitin ligases, and we currently lack ligands to engage the majority of ubiquitin ligases. Furthermore, in cancer cells, acquired resistance to PROTACs can emerge through mutations in the native degradation machinery. Here, we propose a strategy for targeted protein degradation that obviates the need for endogenous degradation enzymes, instead leveraging light-activated, target-localized protein cleavage reactions. Our proposed technology for visible light-catalyzed targeted protein degradation takes advantage of another powerful chemical biology method: photoproximity labeling. Several groups, including our own, have developed light-activatable catalysts that can initiate protein tagging reactions under biological conditions. When these photocatalysts are attached to a drug molecule or antibody, they can be localized to a target protein to selectively tag that target and other molecules in close proximity. Critically, our photocatalysts are activated by deep red light (600-800 nm), which is tissue penetrant and non-toxic. In this project, instead of using photoproximity labeling to tag proteins, we will use this technology to catalyze peptide bond cleavage reactions. Our photocatalysts will be conjugated to highly selective ligands targeting key cancer proteins, and these conjugates will be used to initiate light-catalyzed protein degradation reactions. In Aim 1 of this study, we will optimize the catalytic system and cleavage reactions for high efficiency. In Aim 2, we will demonstrate that this system is compatible with the targeted degradation of a cell surface protein, the immune checkpoint receptor, PD-1. In Aim 3, we will optimize catalysts for the degradation of an intracellular protein, the oncogenic phosphatase SHP2. Successful development of our photocatalytic degradation technology will enable a new strategy to degrade proteins with high spatial and temporal precision. This technique could be used to ablate cancer proteins in live cells or living organisms, to investigate the functions of those proteins or for therapeutic purposes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).