9GK6

ERAP1 in complex with 1-[2-(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl)acetamido]cyclohexane-1-carboxylic acid

This is a non-PDB format compatible entry.

Summary for 9GK6

• Entry DOI: 10.2210/pdb9gk6/pdb
• Descriptor: Endoplasmic reticulum aminopeptidase 1, ZINC ION, D-MALATE, ... (6 entities in total)
• Functional Keywords: erap1, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 107080.95

Authors

Convery, M.,Rowland, P. (deposition date: 2024-08-23, release date: 2025-01-22)

Primary citation

Hryczanek, R.P.,Hackett, A.S.,Rowland, P.,Chung, C.W.,Convery, M.A.,Holmes, D.S.,Hutchinson, J.P.,Kitchen, S.,Korczynska, J.,Law, R.P.,Lea, J.D.,Liddle, J.,Lonsdale, R.,Neu, M.,Nickels, L.,Phillipou, A.,Rowedder, J.E.,Schneck, J.L.,Scott-Stevens, P.,Sheehan, H.,Tayler, C.L.,Temponeras, I.,Tinworth, C.P.,Walker, A.L.,Wojno-Picon, J.,Young, R.J.,Lindsay, D.M.,Stratikos, E.
Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.
Acs Med.Chem.Lett., 15:2107-2114, 2024

PubMed 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.

PubMed: 39691536
DOI: 10.1021/acsmedchemlett.4c00401

Experimental method

X-RAY DIFFRACTION (1.327 Å)