Modulators of hERAP2 discovered by high-throughput screening

Endoplasmic reticulum aminopeptidase 2, ERAP2, is an emerging pharmacological target in cancer immunotherapy and control of autoinflammatory diseases, as it is involved in antigen processing. It has been linked to the risk of development of spondyloarthritis, and it associates with the immune infiltration of tumours and strongly predicts the overall survival for patients receiving check-point inhibitor therapy. While some selective inhibitors of its homolog ERAP1 are available, no selective modulator of ERAP2 has been disclosed so far. In order to identify such compounds, we screened an in-house focused library of 1920 compounds designed to target metalloenzymes. Structure-Activity Relationships and docking around two hits led to the discovery of selective inhibitors of ERAP2. Amid those, some bind to yet untapped amino-acids in the S1 pocket. Importantly, we disclose also the first activator of small substrates hydrolysis by ERAP2. Inhibitors and activators identified in this study could serve as useful starting points for optimization.