Sulfonyl-purine probes for covalent targeting of lysine and tyrosine in drug discovery

Background

A significant portion of the human proteome remains inaccessible to traditional drug discovery approaches, particularly proteins lacking reactive cysteines or well-defined binding pockets. These so-called “undruggable” targets present major challenges for small molecule therapeutics, limiting the development of treatments for many diseases. Current covalent drug design strategies largely rely on cysteine-targeting electrophiles, which suffer from selectivity issues due to cysteine’s widespread distribution and offer limited scope for expanding the druggable proteome. There is a critical need for novel chemistries that can selectively and irreversibly target alternative nucleophilic residues such as lysine and tyrosine, enabling deeper proteome-wide profiling and more diverse therapeutic strategies.

Technology overview

This technology introduces a new class of sulfonyl-purine (SuPUR) com­pounds that covalently modify proteins through a mechanism termed Purine Activated Covalent Targeting (PACT) chemistry. These electrophilic probes consist of a sulfonyl moiety linked to a purine or purine analog, which serves as a leaving group upon reaction with nucleophilic amino acid residues.
SuPUR compounds exhibit high selectivity toward lysine and tyrosine residues, enabling covalent modification at non-catalytic or structurally unique sites across the proteome. This chemistry supports dual applications: as proteomic profiling tools to identify reactive and ligandable sites, and as covalent ligands for the development of selective inhibitors. The compounds demonstrate superior lysine labeling efficiency compared to existing technologies and have successfully been applied to selectively inhibit proteins such as ABAD and ABHD10. SuPUR analogs can also be tuned for regioselective targeting, enabling precise modulation of protein function for therapeutic or investigative purposes.

Benefits

  • Covalently targets lysine and tyrosine residues beyond traditional cysteine sites
  • Enables selective inhibition of previously undruggable protein targets
  • Supports both proteome-wide profiling and ligand development
  • Higher lysine labeling efficiency than alternative methods
  • Regioselective analogs allow for fine-tuned target engagement

Applications

  • Covalent drug discovery
  • Target identification and validation
  • Proteome-wide reactive site mapping
  • Chemical biology tool development
  • Disease-specific inhibitor design

Opportunity

  • Expands the scope of druggable proteins for therapeutic intervention
  • Provides unique inhibitory mechanisms for precision targeting
  • Applicable across oncology, neurodegeneration, and infectious diseases
  • Available for exclusive licensing

Intellectual property

PCT/US2025/030073
Patent Information:
Direct Link:
https://canberra-ip.technologypublisher.com/tech/Sulfonyl-purine_probes_for_c ovalent_targeting_of_lysine_and_tyrosine_in_drug_discovery
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For Information, Contact:
Cory Lago
Intellectual Property Specialist
University of Texas at Austin
cory.lago@austin.utexas.edu