Optimization of potent and selective cyclohexyl acid ERAP1 inhibitors using structure- and property-based drug design

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Hryczanek, Ross P. and Hackett, Andrew S. and Rowland, Paul and Chung, Chun-wa and Convery, Máire A. and Holmes, Duncan S. and Hutchinson, Jonathan P. and Kitchen, Semra and Korczynska, Justyna and Law, Robert P. and Lea, Jonatahn D. and Liddle, John and Lonsdale, Richard and Neu, Margarete and Nickels, Leng and Phillipou, Alex and Rowedder, James E. and Schneck, Jessica L. and Scott-Stevens, Paul and Sheehan, Hester and Tayler, Chloe L. and Temponeras, Ioannis and Tinworth, Christopher P. and Walker, Ann L. and Wojno-Picon, Justyna and Young, Robert J. and Lindsay, David M. and Stratikos, Efstratios (2024) Optimization of potent and selective cyclohexyl acid ERAP1 inhibitors using structure- and property-based drug design. ACS Medicinal Chemistry Letters, 15 (12). 2107–2114. ISSN 1948-5875 (https://doi.org/10.1021/acsmedchemlett.4c00401)

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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 >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.

ORCID iDs

Hryczanek, Ross P., Hackett, Andrew S., Rowland, Paul, Chung, Chun-wa, Convery, Máire A., Holmes, Duncan S., Hutchinson, Jonathan P., Kitchen, Semra, Korczynska, Justyna, Law, Robert P., Lea, Jonatahn D., Liddle, John, Lonsdale, Richard, Neu, Margarete, Nickels, Leng, Phillipou, Alex, Rowedder, James E., Schneck, Jessica L., Scott-Stevens, Paul, Sheehan, Hester, Tayler, Chloe L., Temponeras, Ioannis, Tinworth, Christopher P. ORCID logoORCID: https://orcid.org/0000-0002-2756-707X, Walker, Ann L., Wojno-Picon, Justyna, Young, Robert J., Lindsay, David M. ORCID logoORCID: https://orcid.org/0000-0003-4498-5094 and Stratikos, Efstratios;
CORE (COnnecting REpositories)