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Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design. | LitMetric

AI Article Synopsis

Article Abstract

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound , rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647717PMC
http://dx.doi.org/10.1021/acsmedchemlett.4c00401DOI Listing

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