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

Abstract

In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein–protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.

Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole–Electron Analysis

“…With the high spatiotemporal precision of light, PS-degrons allow controllable knockdown of the target proteins at tumor sites, thus minimizing the systemic toxicity to normal tissues. PS-degrons for targeted protein degradation has currently been validated in several protein targets including estrogen receptors, glutathione peroxidase, and human epidermal growth factor receptors. − …”