Modulators of hERAP2 discovered by high-throughput screening

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• Endoplasmic reticulum aminopeptidase 2 (ERAP2) is implicated in antigen processing, influencing cancer immunotherapy and autoinflammatory diseases.
• ERAP2 is linked to spondyloarthritis risk, tumor immune infiltration, and patient survival in checkpoint inhibitor therapy.
• Selective ERAP1 inhibitors exist, but no selective modulators for ERAP2 have been reported.

Purpose of the Study:

• To discover selective inhibitors and activators of ERAP2.
• To identify novel compounds targeting ERAP2 for therapeutic applications.

Main Methods:

• Screening of an in-house library of 1920 metalloenzyme-targeting compounds.
• Structure-Activity Relationship (SAR) analysis and molecular docking of identified hits.
• Discovery of selective ERAP2 inhibitors and the first ERAP2 activator.

Main Results:

• Identification of selective ERAP2 inhibitors, some targeting novel amino acids in the S1 pocket.
• Discovery of the first small-molecule activator for ERAP2-mediated hydrolysis.
• These findings provide crucial starting points for drug optimization.

Conclusions:

• The study presents the first selective inhibitors and activators of ERAP2.
• These modulators offer potential for developing new therapies for cancer and autoimmune disorders.
• Further optimization of these compounds could lead to advanced therapeutic agents.