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

ABSTRACT: Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-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 >

SUBMITTER: Hryczanek RP 

PROVIDER: S-EPMC11647717 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature