Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

  • J Med Chem. 2024 Jun 25. doi: 10.1021/acs.jmedchem.4c00781.
Simon C C Lucas  1 ,  Alexander G Milbradt  2 ,  J Henry Blackwell  1 ,  Silvia Bonomo  1 ,  Andrew Brierley  3 ,  Doyle J Cassar  4 ,  Jared Freeman  5 ,  Thomas E Hadfield  1 ,  Lucas A Morrill  6 ,  Rick Riemens  7 ,  Sunil Sarda  3 ,  Stefan Schiesser  8 ,  Daniel Wiktelius  9 ,  Samiyah Ahmed  10 ,  Mark J Bostock  2 ,  Ulf Börjesson  11 ,  Claudia De Fusco  1 ,  Carine Guerot  4 ,  David Hargreaves  2 ,  Sarah Hewitt  2 ,  Michelle L Lamb  6 ,  Nancy Su  12 ,  Ryan Whatling  2 ,  Matthew Wheeler  2 ,  Jason G Kettle  4
Affiliations
  • 1. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2. Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3. Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 4. Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 5. Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolic Disorders (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 6. Medicinal Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 7. Medicinal Chemistry, Oncology R&D, Acerta B. V., a Part of the AstraZeneca Group, Oss 5349, The Netherlands.
  • 8. Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 9. Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 10. Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 11. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 12. Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
PMID: 38916990 DOI: 10.1021/acs.jmedchem.4c00781
Abstract

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the Bim peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.

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