9tfn
ERAP1 in complex with (3R,4R)-1-{3-cyano-4-methyl-6-[(4-methyloxan-4-yl)amino]pyridin-2-yl}-4-(propan-2-yl)pyrrolidine-3-carboxylic acid
Structural highlights
FunctionERAP1_HUMAN Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.[1] [2] [3] Publication Abstract from PubMedEndoplasmic reticulum aminopeptidase 1 (ERAP1) regulates immune responses by proteolytically processing peptides presented by major histocompatibility class I molecules (MHC-I). ERAP1 can reduce the immunogenicity of cancer cells by destroying cancer-associated antigenic peptides or contribute to autoimmunity by generating self-antigenic peptides. ERAP1 inhibition has emerged as a tractable approach for cancer immunotherapy and specific classes of autoimmune diseases. We describe the discovery of a potent and selective ERAP1 inhibitor that targets its regulatory allosteric site. The compound has favorable in vivo pharmacokinetics, oral bioavailability, can regulate the immunopeptidome of cancer cells, and enhance tumor antigenicity in vivo controlling growth. When administered in the murine collagen-induced arthritis model, we observed no exacerbation of autoimmune responses but rather a dose-dependent therapeutic benefit. Our results demonstrate that ERAP1 inhibition is a tractable approach to modulating immune responses, provide mechanistic insight, and are valuable in vivo tools for interrogating ERAP1 biology and further drug development. Discovery of an Orally Available Potent ER Aminopeptidase 1 (ERAP1) Inhibitor That Enhances Antitumor Responses and Limits Inflammatory Autoimmunity In Vivo.,Tinworth CP, Wojno-Picon J, Adam M, Gade S, Hancock AP, Hirst DJ, Hutchinson JP, Kitchen S, Koumantou D, Lea J, Lehmann S, Liddle J, Lonsdale R, Neu M, Nickels L, Phillipou A, Rowedder JE, Rowland P, Schneck JL, Scott-Stevens P, Sheehan H, Steidel M, Tayler CL, Temponeras I, Thang K, Tough DF, Vitulli G, Wall ID, Young RJ, Zinn N, Peace S, Stratikos E J Med Chem. 2026 Jun 21. doi: 10.1021/acs.jmedchem.6c00029. PMID:42324823[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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