Chemoproteomics-enabled development of covalent molecular glue degraders for oncogenic transcription factors

• Applicant: Dr. Christian Stieger
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553700363

Misregulation of transcription factors and transcriptional regulators is a major driver of cancer. However, these proteins are notoriously difficult targets for drug discovery, because they often engage in protein-protein or protein-DNA interactions and do not have proper binding pockets. Therefore, targeting transcription factors with classical small molecule drugs is challenging. Molecular glue or other monovalent degraders may be a more promising strategy for drugging these targets. Covalent fragment ligands that do not require deep binding pockets, because the binding is dictated by a combination of reactivity and binding affinity, may serve as attractive starting points for the discovery of monovalent degraders acting on transcription factors. This project aims to systematically identify either molecular glue-based or destabilization-based degraders targeting the oncogenic and highly related transcription factors YAP (Yes-Associated Protein) and TAZ (Transcriptional coActivator with PDZ-binding motif, also known as WWTR1). These two transcriptional regulators are key components of the Hippo and Wnt signaling pathways and are found to be activated in various solid tumors. Despite their significant involvement in various cancers, both proteins are considered “undruggable" and no direct inhibitor or degrader has been reported so far. I will use a curated covalent ligand library in target-based screens using transgenic HiBit-cell lines that facilitate the identification of potential degrader compounds for the target of interest in medium to high throughput. After the identification of potential degrader compounds, I will use chemoproteomic and functional genomic approaches to deconvolute the mechanism of action of the obtained screening hits. The most promising hits will be further investigated for their proteome-wide selectivity. Moreover, I will perform some chemical optimization of the compound structure to obtain promising lead candidates for future drug discovery. The anticipated discovery does not only provide a potential starting point for the development of future cancer therapeutics, but will also provide the scientific community with valuable tool-compounds to study oncogenic transcription factors without the need for genetic manipulation.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Daniel Nomura