Investigating the phosphinic acid tripeptide mimetic DG013A as a tool compound inhibitor of the M1-aminopeptidase ERAP1

被引：3

作者：

Wilding, Birgit ^{[1
]}

Pasqua, A. Elisa ^{[1
]}

Chessum, Nicola E. A. ^{[1
]}

Pierrat, Olivier A. ^{[1
]}

Hahner, Tamas ^{[1
]}

Tomlin, Kathy ^{[1
]}

Shehu, Erald ^{[1
]}

Burke, Rosemary ^{[1
]}

Richards, G. Meirion ^{[1
]}

Whitton, Bradleigh ^{[1
]}

Arwert, Esther N. ^{[1
]}

Thapaliya, Arjun ^{[1
,2
]}

Salimraj, Ramya ^{[1
,2
]}

van Montfort, Rob ^{[1
,2
]}

Skawinska, Agi ^{[1
]}

Hayes, Angela ^{[1
]}

Raynaud, Florence ^{[1
]}

Chopra, Rajesh ^{[1
]}

Jones, Keith ^{[1
]}

Newton, Gary ^{[1
]}

Cheeseman, Matthew D. ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Canc Therapeut Unit, London SW7 3RP, England

[2] Inst Canc Res, Div Struct Biol, London SW7 3RP, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2021年 / 42卷

关键词：

ERAP1; DG013A; Chemical probe; M1-aminopeptidase; Permeability; MHC CLASS-I; AMINOPEPTIDASE;

D O I：

10.1016/j.bmcl.2021.128050

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

ERAP1 is a zinc-dependent M1-aminopeptidase that trims lipophilic amino acids from the N-terminus of peptides. Owing to its importance in the processing of antigens and regulation of the adaptive immune response, dysregulation of the highly polymorphic ERAP1 has been implicated in autoimmune disease and cancer. To test this hypothesis and establish the role of ERAP1 in these disease areas, high affinity, cell permeable and selective chemical probes are essential. DG013A 1, is a phosphinic acid tripeptide mimetic inhibitor with reported low nanomolar affinity for ERAP1. However, this chemotype is a privileged structure for binding to various metaldependent peptidases and contains a highly charged phosphinic acid moiety, so it was unclear whether it would display the high selectivity and passive permeability required for a chemical probe. Therefore, we designed a new stereoselective route to synthesize a library of DG013A 1 analogues to determine the suitability of this compound as a cellular chemical probe to validate ERAP1 as a drug discovery target.

引用

页数：5