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

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.