Reactive fragments targeting carboxylate residues employing direct to biology, high-throughput chemistry

Ross P. Thomas, Emma K. Grant, Eleanor R. Dickinson, Francesca Zappacosta, Lee J. Edwards, Michael M. Hann, David House, Nicholas C. O. Tomkinson*, Jacob T. Bush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
42 Downloads (Pure)

Abstract

The screening of covalent or ‘reactive’ fragment libraries against proteins is becoming an integral approach in hit identification, enabling the development of targeted covalent inhibitors and tools. To date, reactive fragment screening has been limited to targeting cysteine residues, thus restricting applicability across the proteome. Carboxylate residues present a unique opportunity to expand the accessible residues due to high proteome occurrence (∼12%). Herein, we present the development of a carboxylate-targeting reactive fragment screening platform utilising 2-aryl-5-carboxytetrazole (ACT) as the photoreactive functionality. The utility of ACT photoreactive fragments (ACT-PhABits) was evaluated by screening a 546-membered library with a small panel of purified proteins. Hits identified for BCL6 and KRASG12D were characterised by LC-MS/MS studies, revealing the selectivity of the ACT group. Finally, a photosensitised approach to ACT activation was developed, obviating the need for high energy UV-B light.
Original languageEnglish
Pages (from-to)671-679
Number of pages9
JournalRSC Medicinal Chemistry
Volume14
Issue number4
Early online date22 Feb 2023
DOIs
Publication statusE-pub ahead of print - 22 Feb 2023

Keywords

  • targeted covalent inhibitors
  • reactive fragment screening
  • carboxylate residues

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