Ligand-Directed Photodegradation of Interacting Proteins: Oxidative HER2/HER3 Heterodimer Degradation with a Lapatinib-Derived Photosensitizer

Inthis work, we described a photocatalytic approach, termed ligand-directedphotodegradation of interacting proteins (LDPIP), for efficient protein-proteinheterodimer degradation. This LDPIP approach utilizes a combinationof a photosensitizing protein ligand and appropriate light and molecularoxygen to induce oxidative damage to the ligand-binding protein aswell as its interacting protein partner. As a showcase study, a photosensitizingHER2 ligand HER-PS-I was rationally designed based onthe FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2together with its interacting protein partner HER3, which is thoughtto induce HER2-targeted therapy resistance and difficult to targetby small molecules. HER-PS-I exhibited excellent anticanceractivity against drug-resistant MDA-MB-453 cells and its three-dimensionalmulticellular spheroids. We hope that this LDPIP approach would findmore applications in degrading proteins that are thought undruggableor difficult to drug.

Automated summary

This work presents a photocatalytic approach called ligand-directed photodegradation of interacting proteins (LDPIP) for efficient degradation of protein-protein heterodimers. LDPIP utilizes a photosensitizing protein ligand, appropriate light, and molecular oxygen to induce oxidative damage to both the ligand-binding protein and its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was designed based on the FDA-approved HER2 inhibitor lapatinib to degrade HER2 and its difficult-to-target interacting protein partner HER3. HER-PS-I exhibited excellent anticancer activity in drug-resistant MDA-MB-453 cells and multicellular spheroids. The LDPIP approach holds promise for degrading undruggable or difficult-to-drug proteins.