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ERAP1 in complex with 1-[2-(6-bromo-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamido]-4,4-difluorocyclohexane-1-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) 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 >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound 7, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization. Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.,Hryczanek RP, Hackett AS, Rowland P, Chung CW, Convery MA, Holmes DS, Hutchinson JP, Kitchen S, Korczynska J, Law RP, Lea JD, Liddle J, Lonsdale R, Neu M, Nickels L, Phillipou A, Rowedder JE, Schneck JL, Scott-Stevens P, Sheehan H, Tayler CL, Temponeras I, Tinworth CP, Walker AL, Wojno-Picon J, Young RJ, Lindsay DM, Stratikos E ACS Med Chem Lett. 2024 Nov 6;15(12):2107-2114. doi: , 10.1021/acsmedchemlett.4c00401. eCollection 2024 Dec 12. PMID:39691536[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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