Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots.

Area of Science:

• Proteomics
• Chemical Biology
• Drug Discovery

Background:

• Human genome sequencing promised disease cures, but many disease-controlling proteins remain difficult drug targets.
• These challenging targets often lack screening assays or accessible binding pockets, hindering small-molecule drug development.

Purpose of the Study:

• To discuss modern activity-based protein profiling (ABPP) chemoproteomic strategies.
• To highlight methods for mapping 'ligandable' hotspots in proteomes.
• To demonstrate the pharmacological interrogation of previously intractable protein targets.

Main Methods:

• Utilizing activity and reactivity-based chemical probes for ABPP.
• Employing chemoproteomic strategies to profile proteomes.
• Developing selective small-molecule inhibitors against disease-related targets.

Main Results:

• Successful identification of 'ligandable' hotspots within proteomes.
• Development of highly selective small-molecule inhibitors against challenging disease targets.
• Demonstration of ABPP's utility in drug discovery for difficult targets.

Conclusions:

• Modern ABPP-based chemoproteomic strategies are effective for targeting difficult proteins.
• These approaches facilitate the pharmacological interrogation of previously undruggable targets.
• The presented technologies offer a promising avenue for developing novel therapeutics.