NU 2014-002

Inventors

Alexander V. Statsyk*

Stefan G. Kathman

Short Description

An unbiased library of compounds was generated using a one-step method in order to screen for covalent inhibitors of enzymes

Abstract

Enzyme inhibitors that covalently modify their target are gaining in popularity due to their high potency even at low doses and lack of susceptibility to resistance mutations. However, it was difficult to identify potential covalent inhibitors using currently available high-throughput techniques because the compound libraries are often based on reversible inhibitor scaffolds. Researchers from Northwestern University have developed an alternate strategy, called irreversible tethering, which allows for high-throughput screening of cysteine-reactive covalent inhibitors. This technique will enable the identification of novel irreversible enzyme inhibitors. In fact, two covalent inhibitors for papain and the 'undruggable' target Nedd4-1, have already been identified via this method. This novel screening method is superior to others because library compounds can be synthesized in a single step, hits are specific and leads can be optimized without removing irreversible tethers.

Applications

• Identification of irreversible inhibitors of cysteine-containing proteins
• Identification of covalent inhibitors of protein-protein interactions
• Identification of inhibitors for 'undruggable' targets

Advantages

• Rapid, specific high-throughput screen
• One-step synthesis of library compounds
• Simplified drug lead optimization as tether can be retained

Publications

Kathman S, Xu Z, Statsyuk A (2014) A Fragment-based Method to Discover Irreversible Covalent Inhibitors of Cysteine Proteases. Journal of Medical Chemistry. 57(11): 4969-74.

IP Status

Provisional US patent application has been filed.