A road map for prioritizing warheads for cysteine targeting covalent inhibitors - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2018

A road map for prioritizing warheads for cysteine targeting covalent inhibitors

Peter Abranyi-Balogh
  • Fonction : Auteur
Laszlo Petri
  • Fonction : Auteur
Timea Imre
  • Fonction : Auteur
Peter Szijj
  • Fonction : Auteur
Andrea Scarpino
  • Fonction : Auteur
Ana Mitrovic
  • Fonction : Auteur
Ursa Petar Fonovic
  • Fonction : Auteur
Krisztina Nemeth
  • Fonction : Auteur
David I. Roper
  • Fonction : Auteur
Kata Horvati
  • Fonction : Auteur
Gyorgy G. Ferenczy
  • Fonction : Auteur
Janko Kos
  • Fonction : Auteur
Janez Ilas
  • Fonction : Auteur
Gyorgy M. Keseru
  • Fonction : Auteur

Résumé

Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently. In contrast, we suggest that the reactive warhead itself should be tailored to the reactivity of the specific cysteine being targeted, and we describe a strategy to achieve this goal. Here, we have extended and systematically explored the available organic chemistry toolbox and characterized a large number of warheads representing different chemistries. We demonstrate that in addition to the common Michael addition, there are other nucleophilic addition, addition-elimination, nucleophilic substitution and oxidation reactions suitable for specific covalent protein modification. Importantly, we reveal that warheads for these chemistries impact the reactivity and specificity of covalent fragments at both protein and proteome levels. By integrating surrogate reactivity and selectivity models and subsequent protein assays, we define a road map to help enable new or largely unexplored covalent chemistries for the optimization of cysteine targeting inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.
Fichier non déposé

Dates et versions

hal-02175119 , version 1 (05-07-2019)

Identifiants

Citer

Peter Abranyi-Balogh, Laszlo Petri, Timea Imre, Peter Szijj, Andrea Scarpino, et al.. A road map for prioritizing warheads for cysteine targeting covalent inhibitors. European Journal of Medicinal Chemistry, 2018, 160, pp.94--107. ⟨10.1016/j.ejmech.2018.10.010⟩. ⟨hal-02175119⟩
239 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More