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Lookup NU author(s): Dr Catherine Salvini, Benoit Darlot, Jack Davison, Dr Mathew Martin, Dr Susan Tudhope, Dr Shannon TurbervilleORCiD, Professor Akane Kawamura, Professor Martin NobleORCiD, Professor Steve Wedge, Professor Mike Waring
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Optimisation of the affinity of lead compounds is a critical challenge in the identification of drug candidates and chemical probes and is a process that takes many years. Fragment-based drug discovery has become established as one of the methods of choice for drug discovery starting with small, low affinity compounds. Due to their low affinity, the evolution of fragments to desirable levels of affinity is often a key challenge. The accepted best method for increasing the potency of fragments is by iterative fragment growing, which can be very time consuming and complex. Here, we introduce a paradigm for fragment hit optimisation using poised DNA-encoded chemical libraries (DELs). The synthesis of a poised DEL, a partially constructed library that retains a reactive handle, allows the coupling of any active fragment for a specific target protein, allowing rapid discovery of potent ligands. This is illustrated for bromodomain-containing protein 4 (BRD4), in which a weakly binding fragment was coupled to a 42-member poised DEL via Suzuki–Miyaura cross coupling resulting in the identification of an inhibitor with 51 nM affinity in a single step, representing an increase in potency of several orders of magnitude from an original fragment. The potency of the compound was shown to arise from the synergistic combination of substructures, which would have been very difficult to discover by any other method and was rationalised by X-ray crystallography. The compound showed attractive lead-like properties suitable for further optimisation and demonstrated BRD4-dependent cellular pharmacology. This work demonstrates the power of poised DELs to rapidly optimise fragments, representing an attractive generic approach to drug discovery.
Author(s): Salvini CLA, Darlot B, Davison J, Martin MP, Tudhope SJ, Turberville S, Kawamura A, Noble MEM, Wedge SR, Crawford JJ, Waring MJ
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2023
Volume: 14
Issue: 31
Pages: 8288-8294
Online publication date: 12/07/2023
Acceptance date: 11/07/2023
Date deposited: 20/07/2023
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/D3SC01171B
DOI: 10.1039/D3SC01171B
Data Access Statement: Crystallographic data for 22 has been deposited at the PBD under 8C11. The datasets supporting this article have been uploaded as part of the ESI. Electronic supplementary information (ESI) available: Detailed experimental procedures for synthesis and selection of the libraries and off-DNA synthesis, protein production SPR testing, crystallography and cellular pharmacology. See DOI: https://doi.org/10.1039/d3sc01171b
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