Cell Chemical Biology

IFNα primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization

The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex. Biophysical and structural biology studies confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome as well as pathway analyses suggest possible explanations for the observed synergistic effect of IFNα/FC treatment on cancer cells. This study elucidates the polypharmacological effects of FCs in cancer cells and identifies potential targets from the vast interactome of 14-3-3s for therapeutic intervention in oncology.

VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation

In targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which de facto have strictly limited expression to diseased cells. Here, we provide proof-of-concept for viral E3 pan-essential removing targeting chimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.