Reimagining Druggability Using Chemoproteomic Platforms

Area of Science:

• Chemical biology
• Proteomics
• Drug discovery

Background:

• The majority of the human proteome remains
• undruggable
• due to the lack of well-defined binding pockets for small molecules.
• Innovative strategies are needed to target these proteins.
• Current drug discovery efforts face significant bottlenecks in addressing this challenge.

Purpose of the Study:

• To highlight the role of chemoproteomic platforms, particularly activity-based protein profiling (ABPP), in overcoming the challenge of the undruggable proteome.
• To showcase how these platforms enable the discovery of novel therapeutic targets and modalities.
• To discuss the future impact of chemoproteomics on drug discovery and therapeutic development.

Main Methods:

• Utilizing reactivity-based chemical probes to identify
• ligandable hotspots
• on proteins.
• Employing advanced quantitative mass spectrometry-based proteomic approaches.
• Applying chemoproteomic insights to develop covalent ligands and targeted protein degradation systems.

Main Results:

• Identification of proteome-wide sites (
• ligandable hotspots
• ) amenable to small-molecule targeting.
• Discovery of unique allosteric sites and intrinsically disordered regions for therapeutic intervention.
• Expansion of targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) through new E3 ligase recruiters.

Conclusions:

• Chemoproteomic approaches are crucial for tackling the undruggable proteome.
• These platforms facilitate the discovery of novel binders and therapeutic modalities, including TPD and PROTACs.
• Future applications include proteome-wide ligandability mapping and the development of next-generation small-molecule therapeutics.