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A road map for prioritizing warheads for cysteine targeting covalent inhibitors
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Ábrányi-Balogh, Péter, Petri, László, Imre, Tímea, Szijj, Péter, Scarpino, Andrea, Hrast, Martina, Mitrović, Ana, Fonovič, Urša Pečar, Németh, Krisztina, Barreteau, Hélène, Roper, David I., Horváti, Kata, Ferenczy, György G, Kos, Janko, Ilaš, Janez, Gobec, Stanislav and Keserű, György M (2018) A road map for prioritizing warheads for cysteine targeting covalent inhibitors. European Journal of Medicinal Chemistry, 160 . pp. 94-107. doi:10.1016/j.ejmech.2018.10.010
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Official URL: https://doi.org/10.1016/j.ejmech.2018.10.010
Abstract
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. [Abstract copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.]
| Item Type: | Journal Article | ||||||||
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| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||||
| SWORD Depositor: | Library Publications Router | ||||||||
| Journal or Publication Title: | European Journal of Medicinal Chemistry | ||||||||
| Publisher: | Elsevier Masson | ||||||||
| ISSN: | 0223-5234 | ||||||||
| Official Date: | December 2018 | ||||||||
| Dates: |
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| Volume: | 160 | ||||||||
| Page Range: | pp. 94-107 | ||||||||
| DOI: | 10.1016/j.ejmech.2018.10.010 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access |
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