Fragment expansion with NUDELs – poised DNA-encoded libraries

Journal article

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.

Authors: Salvini, CLA; Darlot, B; Davison, J; Martin, MP; Tudhope, SJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Chemical Science
• Volume: 14
• Issue: 31
• Pages: 8288-8294
• Publication date: 2023-08-09
• DOI: 10.1039/d3sc01171b
• EISSN: 2041-6539
• ISSN: 2041-6520
• Language: English
• Keywords: Computer science; Biochemistry; Histone; Chemistry; Identification (biology); Potency; Computational biology; Drug discovery; In vitro; Combinatorial chemistry; Fragment (logic); DNA; Stereochemistry; Bromodomain; Biology; Algorithm