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

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Thomas, Ross P. and Grant, Emma K. and Dickinson, Eleanor R. and Zappacosta, Francesca and Edwards, Lee J. and Hann, Michael M. and House, David and Tomkinson, Nicholas C. O. and Bush, Jacob T. (2023) Reactive fragments targeting carboxylate residues employing direct to biology, high-throughput chemistry. RSC Medicinal Chemistry, 14 (4). pp. 671-679. ISSN 2632-8682 (https://doi.org/10.1039/d2md00453d)

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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.

ORCID iDs

Thomas, Ross P., Grant, Emma K., Dickinson, Eleanor R., Zappacosta, Francesca, Edwards, Lee J., Hann, Michael M., House, David, Tomkinson, Nicholas C. O. ORCID logoORCID: https://orcid.org/0000-0002-5509-0133 and Bush, Jacob T.;
  • Item type:Article
    ID code:84444
    Dates:
    Date
    Event
    22 February 2023
    Published
    22 February 2023
    Published Online
    30 January 2023
    Accepted
    20 December 2022
    Submitted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:28 Feb 2023 14:19
    Last modified:18 Dec 2024 17:55
    URI:https://strathprints.strath.ac.uk/id/eprint/84444
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