Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development.

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Targeted protein degradation (TPD) is a promising therapeutic strategy for drug development, enabling targeting of previously inaccessible proteins.
• Current degrader discovery is inefficient due to limited understanding of the molecular events governing target degradation.
• Identifying key factors for successful protein degradation is crucial for advancing TPD approaches.

Purpose of the Study:

• To annotate the degradable kinome using chemoproteomics and identify chemical leads for kinase degrader discovery.
• To investigate the fundamental mechanisms of the ubiquitin proteasome system in kinase degradation.
• To develop a framework for evaluating TPD across gene families.

Main Methods:

• Utilized chemoproteomics to profile the degradable kinome, generating a dataset of chemical leads for approximately 200 kinases.
• Developed and employed multi-targeted degraders to probe the ubiquitin proteasome system.
• Investigated the role of p97 in kinase degradation.

Main Results:

• Generated chemical leads for ~200 kinases, demonstrating that high-potency binding does not guarantee degradation efficacy.
• Uncovered that kinase degradation is dependent on the p97 protein.
• Provided a dataset and methodology applicable to broader gene family TPD evaluation.

Conclusions:

• The study provides a valuable resource for kinase degrader discovery and highlights the ineffectiveness of solely relying on binding potency.
• Established p97 as a key factor in kinase degradation, offering mechanistic insights into TPD.
• Offers a blueprint for systematic TPD evaluation across gene families, accelerating TPD research beyond kinases.