Chemical rewiring of E3 ubiquitin ligases as a generalizable therapeutic approach

Introduction

Classical drug design relies mostly on the availability of accessible pockets to block specific protein activities. Despite tremendous progress, more than 80% of all human proteins remain beyond the reach of traditional inhibitor-centric approaches. Chemical ablation of protein abundance using bivalent degraders (PROTACs) moves away from an occupancy-driven (inhibition) to an event-driven (binding) pharmacology. However, their design is intrinsically limited to targets that are ligandable via chemical probes. To tackle current unmet clinical problems, we need transformative paradigms.

Potential of Monovalent Degraders

Fortuitous discoveries have illustrated the immense potential of monovalent degraders. These molecules induce the degradation of target proteins by:

• Molecular gluing to E3 ubiquitin ligases
• Prompting their destabilization

They have desirable drug-like properties, proven capacity to induce the degradation of proteins otherwise deemed undruggable, and they are already a clinical reality. However, their discovery has been driven by serendipity, thereby hampering their realization as a generalizable drug solution.

Objectives of TrickE3

TrickE3 seeks to establish the foundations for the systematic development of monovalent degraders. To this end, we will:

1. Develop innovative methodologies to detect and predict drug-induced changes in the interactome/activity of E3s at scale.
2. Focus on the chemical rewiring of E3s expressed in pancreatic ductal adenocarcinoma (PDAC) due to the imperative need for treatments.
3. Prospectively identify monovalent degraders (i) of specific vulnerabilities, and (ii) to unlock new PDAC targets.

Impact on Drug Discovery

At the interface of chemical biology and cancer research, TrickE3 will be an instrumental resource to:

• Broaden drug discovery efforts
• Probe disease-relevant vulnerabilities
• Widen the targetable space of the human proteome

We hope to empower other disciplines to chemically explore, without limits, the degradation of relevant targets.