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

Autor: Wilding B; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Pasqua AE; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., E A Chessum N; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Pierrat OA; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Hahner T; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Tomlin K; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Shehu E; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Burke R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Richards GM; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Whitton B; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Arwert EN; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Thapaliya A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK; Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK., Salimraj R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK; Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK., van Montfort R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK; Division of Structural Biology, The Institute of Cancer Research, London SW7 3RP, UK., Skawinska A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Hayes A; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Raynaud F; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Chopra R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Jones K; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Newton G; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK., Cheeseman MD; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SW7 3RP, UK. Electronic address: Matthew.Cheeseman@icr.ac.uk.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Jun 15; Vol. 42, pp. 128050. Date of Electronic Publication: 2021 Apr 20.
DOI: 10.1016/j.bmcl.2021.128050
Abstrakt: 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 metal-dependent 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.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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