Optimization\nof Potent and Selective Cyclohexyl Acid\nERAP1 Inhibitors Using Structure- and Property-Based Drug Design

Endoplasmic reticulum\naminopeptidase 1 (ERAP1) cleaves the <i>N</i>-terminal amino\nacids of peptides, which can then bind\nonto major histocompatibility class I (MHC-I) molecules for presentation\nonto the cell surface, driving the activation of adaptive immune responses.\nIn cancer, overtrimming of mature antigenic peptides can reduce cytotoxic\nT-cell responses, and ERAP1 can generate self-antigenic peptides which\ncontribute to autoimmune cellular responses. Therefore, modulation\nof ERAP1 activity has potential therapeutic indications for cancer\nimmunotherapy and in autoimmune disease. Herein we describe the hit-to-lead\noptimization of a series of cyclohexyl acid ERAP1 inhibitors, found\nby X-ray crystallography to bind at an allosteric regulatory site.\nStructure-based drug design enabled a >1,000-fold increase in ERAP1\nenzymatic and cellular activity, resulting in potent and selective\ntool molecules. For lead compound <b>7</b>, rat pharmacokinetic\nproperties showed moderate unbound clearance and oral bioavailability,\nthus highlighting the promise of the series for further optimization.