Identification of ligands for E3 ligases with restricted expression using fragment-based methods

Area of Science:

• Chemical Biology
• Molecular Biology
• Drug Discovery

Background:

• Heterobifunctional molecules inducing targeted degradation are vital tools in chemical biology and drug discovery.
• The field's progress is limited by a scarcity of available ligands for E3 ligases.
• Expanding the E3 ligase ligand repertoire can broaden the scope of targeted degradation.

Purpose of the Study:

• Identify novel ligands for non-essential E3 ligases.
• Discover ligands preferentially expressed in cancer tissues compared to normal tissues.
• Develop starting points for tumor-selective degraders to enhance the therapeutic window.

Main Methods:

• Protein-observed NMR-based fragment screening to identify fragment ligands.
• X-ray crystallography to characterize the binding modes of identified ligands.

Main Results:

• Identified fragment ligands for non-essential E3 ligases.
• Characterized ligand binding modes using X-ray crystallography.
• These ligands show preferential expression in cancer tissues.

Conclusions:

• The identified ligands are promising starting points for optimizing tumor-selective degraders.
• This approach may lead to targeted degradation therapies with an improved therapeutic window.
• Expanding E3 ligase ligands can advance targeted degradation for cancer treatment.